Efficacy and safety of linagliptin co-administered with low-dose metformin once daily versus high-dose metformin twice daily in treatment-naive patients with type 2 diabetes: a double-blind randomized trial.
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ABSTRACT: Introduction
The aim of this study was to investigate the efficacy and safety of linagliptin + low-dose (LD) metformin once daily versus high-dose (HD) metformin twice daily in treatment-naïve patients with type 2 diabetes.Methods
Patients (n = 689) were randomized (1:1) to double-blind treatment with linagliptin 5 mg + LD metformin (1000 mg) or HD metformin (2000 mg) for 14 weeks. Metformin was initiated at 500 mg/day and up-titrated within 2 weeks; the dose then remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to Week 14 in patients who tolerated a daily metformin dose of ≥1000 mg after 2 weeks.Results
At Week 14, HbA1c changed from a mean baseline of 8.0% (64 mmol/mol) by -0.99% (-11 mmol/mol) for linagliptin + LD metformin, and -0.98% (-11 mmol/mol) for HD metformin [treatment difference -0.01% (95% confidence interval -0.13, 0.12) (0 mmol/mol), P = 0.8924]. The proportion of patients who achieved HbA1c <7.0% (53 mmol/mol) without occurrence of moderate or severe gastrointestinal (GI) events (including abdominal pain, nausea, vomiting, diarrhea, and decreased appetite) was the same in both groups (51.3% for both). Although the occurrence of moderate or severe GI events was similar, the linagliptin + LD metformin group had fewer mild GI events (18.5% versus 24.3%). The incidence of hypoglycemia was low in both groups.Conclusion
Linagliptin + LD metformin combination showed similar efficacy and safety to HD metformin. This combination may be an alternative treatment option in patients who may have difficulty tolerating metformin doses >1000 mg/day.Funding
Boehringer Ingelheim.
SUBMITTER: Ji L
PROVIDER: S-EPMC4376958 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundUmeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD).MethodsThis was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 μg administered once daily (QD), and UMEC 15.6 μg and 31.25 μg administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-label treatment arm. The primary efficacy endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary efficacy endpoints included weighted mean FEV1 over 0-24 hours after morning dosing on Day 7, and serial FEV1 at each time point over 24 hours after morning dosing on Day 7. Safety and pharmacokinetics were also examined.ResultsOne hundred and sixty-three patients (mean age 59.5 years, 52% female) were randomised. Based on the population dose-response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 μg (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 μg QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 μg and below. UMEC 125 μg QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV1 over 0-12 hours were similar to those observed over 12-24 hours after the second dose of UMEC was administered. UMEC was rapidly absorbed following inhaled dosing and eliminated from plasma. Adverse events, generally mild, were highest with UMEC 125 μg QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5-12%).ConclusionsUMEC is a potent QD bronchodilator with geometric mean ED50 of 37 μg. A dose ordering over the range of UMEC 15.6-125 μg QD doses was observed, with UMEC 125 μg showing the greatest improvement in trough FEV1.
| S-EPMC4029330 | biostudies-literature
Project description:Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration-time curve (AUC) 0-24 and Ctrough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9-1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m2. The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91-1.04). The geometric means (%CV) of Ctrough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of Ctrough was 0.89 (90%CI 0.82-0.98), which was below 0.9. The newly calculated target Ctrough level of OD TAC was 4.8-6.2 ng/mL. The best abbreviated AUC0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) - 4.26. The GMR AUC0-24 was within the range of 0.9-1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of Ctrough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC0-24 regardless of CYP3A5 genotypic polymorphism. However, the Ctrough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002).
| S-EPMC9203451 | biostudies-literature
Project description:Approximately 20% to 40% of patients with gastroesophageal reflux disease (GERD) are refractory to standard-dose proton-pump inhibitor (PPI) treatment.We compared the efficacy and quality-of-life effects of 20 mg once daily (QD) versus 10 mg twice daily (BID) rabeprazole (RPZ) in patients with refractory GERD-related symptoms and sleep disturbances.This multicenter, prospective, randomized, open-label study included patients in whom PPI treatment >4 weeks was ineffective. According to the Global Overall Symptom (GOS) scale, PPI-refractory GERD was defined as ?1 category with >3 points among 10 specific upper gastrointestinal symptoms. Seventy-eight patients were randomly assigned to 20 mg QD and 10 mg BID RPZ groups for 8 weeks. Efficacy was evaluated using self-reported questionnaires, including the GOS scale and Pittsburg Sleep Quality Index (PSQI), whereas quality of life was assessed using the Short-Form 8 Health Survey (SF-8), at 4 and 8 weeks. Patients showing improvement at 8 weeks received follow-up every 4 to 8 weeks.GOS scale scores were significantly improved at 8 weeks in both groups, with no significant intergroup differences. Although SF-8 scores showed an increasing trend over 8 weeks in both groups, the physical component summaries in the 10 mg BID group significantly improved. The mental component summaries clearly improved in the 10 mg BID group. Of the 74 cases (4 missing), 51 (68.9%) had PSQI scores ?5.5. PSQI scores remained unchanged during follow-up in both groups. The recurrence rate was not significantly different (46.1% vs 47.1% in the 20 mg QD and 10 mg BID groups, respectively) during the follow-up period at median (interquartile range) 24.0 (30.5) months.In patients with refractory GERD, there was no significant difference in GOS scale score, PSQI, or recurrence rate between the groups. With regard to subscores of the SF-8, the 10 mg BID group might be potentially effective.
| S-EPMC5200872 | biostudies-other
Project description:Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed.New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve.Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6-8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation.Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties), formulations of bimatoprost 0.01% can be administered once or twice daily. These findings support development of bimatoprost 0.01%-based fixed-dose combination therapies administered twice daily for patients who require multiple adjunctive medications to control their IOP.
| S-EPMC5627754 | biostudies-other
Project description:BackgroundTacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD.MethodsA cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA.ResultsConversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p = 0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort.ConclusionsThe CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements.Trial registrationClinical trials.gov identifier: NCT01884480.
| S-EPMC4730664 | biostudies-literature
Project description:This open-label study aimed to compare once-daily and twice-daily pramipexole extended release (PER) treatment in Parkinson's disease (PD). PD patients on dopamine agonist therapy, but with unsatisfactory control, were enrolled. Existing agonist doses were switched into equivalent PER doses. Subjects were consecutively enrolled into either once-daily-first or twice-daily-first groups and received the prescribed amount in one or two, respectively, daily doses for 8 weeks. For the second period, subjects switched regimens in a crossover manner. The forty-four patients completed a questionnaire requesting preference during their last visit. We measured the UPDRS-III, Hoehn and Yahr stages (H&Y) in medication-on state, Parkinson's disease sleep scale (PDSS), and Epworth Sleepiness Scale. Eighteen patients preferred a twice-daily regimen, 12 preferred a once-daily regimen, and 14 had no preference. After the trial, 14 subjects wanted to be on a once-daily regimen, 25 chose a twice-daily regimen, and 5 wanted to maintain the prestudy regimen. Main reasons for choosing the twice-daily regimen were decreased off-duration, more tolerable off-symptoms, and psychological stability. The mean UPDRS-III, H&Y, and PDSS were not different. Daytime sleepiness was significantly high in the once-daily regimen, whereas nocturnal hallucinations were more common in the twice-daily. Multiple dosing should be considered if once-daily dosing is unsatisfactory. This study is registered as NCT01515774 at ClinicalTrials.gov.
| S-EPMC5318624 | biostudies-literature
Project description:BackgroundInhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD) evening and twice-daily (BD) regimens of the novel inhaled corticosteroid fluticasone furoate (FF) in asthma patients.MethodsPatients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1) 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml) were randomized to FF or fluticasone propionate (FP) regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough) FEV1; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs) and 24-hour urinary cortisol excretion were assessed.ResultsThe intent-to-treat population comprised 147 (FF) and 43 (FP) patients. On Day 28, pre-dose FEV1 showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml) to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml); all FF and FP regimens were significantly superior to placebo (p ≤ 0.02). AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02).ConclusionsFF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose.Trial registrationClinicaltrials.gov; NCT00766090.
| S-EPMC3282675 | biostudies-literature
Project description:BackgroundAntiretroviral therapy (ART) adherence is critical for successful HIV treatment outcomes. Once-daily dosing could improve adherence. Plasma concentrations of once-daily vs twice-daily abacavir + lamivudine are bioequivalent in children, but no randomized trial has compared virological outcomes.MethodsChildren taking abacavir + lamivudine-containing first-line regimens twice daily for more than 36 weeks in the ARROW trial (NCT02028676, ISRCTN24791884) were randomized to continue twice-daily vs move to once-daily abacavir + lamivudine (open-label). Co-primary outcomes were viral load suppression at week 48 (12% noninferiority margin, measured retrospectively) and lamivudine or abacavir-related grade 3/4 adverse events.ResultsSix hundred and sixty-nine children (median 5 years, range 1-16) were randomized to twice daily (n = 333) vs once daily (n = 336) after median 1.8 years on twice-daily abacavir + lamivudine-containing first-line ART. Children were followed for median 114 weeks. At week 48, 242/331 (73%) twice daily vs 236/330 (72%) once daily had viral load less than 80 copies/ml [difference -1.6% (95% confidence interval -8.4,+5.2%) P = 0.65]; 79% twice daily vs 78% once daily had viral load less than 400 copies/ml (P = 0.76) (week 96 results similar). One grade 3/4 adverse event was judged uncertainly related to abacavir + lamivudine (hepatitis; once daily). At week 48, 9% twice daily vs 10% once daily reported missing one or more ART pills in the last 4 weeks (P = 0.74) and 8 vs 8% at week 96 (P = 0.90). Carers strongly preferred once-daily dosing. There was no difference between randomized groups in postbaseline drug-resistance mutations or drug-susceptibility; WHO 3/4 events; ART-modifying, grade 3/4 or serious adverse events; CD4% or weight-for-age/height-for-age (all P > 0.15).ConclusionOnce-daily abacavir + lamivudine was noninferior to twice daily in viral load suppression, with similar resistance, adherence, clinical, immunological and safety outcomes. Abacavir + lamivudine provides the first once-daily nucleoside backbone across childhood that can be used to simplify ART.
| S-EPMC6217915 | biostudies-literature
Project description:OBJECTIVES:To investigate the pharmacokinetics of darunavir/ritonavir and raltegravir, in HIV-infected subjects, in both plasma and at the intracellular (IC) site of action. METHODS:HIV-infected patients on antiretroviral therapy received raltegravir 400 mg twice daily for 21 days (period 1); darunavir/ritonavir 800/100 mg once daily was added for 14 days (period 2), and patients were randomized to continue raltegravir twice daily (group 1) or to switch to 800 mg once daily (group 2), then they all stopped raltegravir intake and continued darunavir/ritonavir once daily for 14 days (period 3). Drug concentrations in plasma and cells (peripheral blood mononuclear cell) were measured, and differences in geometric mean ratios (GMR) and 90% confidence intervals (CI) between period 2 versus period 3 and period 2 versus period 1 were assessed. RESULTS:Twenty-four patients completed the study. Group 1 GMR (90% CI) of darunavir area under the curve (AUC) with and without raltegravir was 1.24 (1.13 to 1.45) for plasma and 1.24 (1.07 to 1.73) for cells and for group 2 was 1.14 (1.07 to 1.24) and 1.03 (0.94 to 1.16). GMR (90% CI) of raltegravir AUC without and with darunavir/ritonavir (plasma and cells) for group 1 was 0.90 (0.73 to 1.44) and 1.02 (0.81 to 1.67) and for group 2 was 1.21 (1.03 to 1.77) and 1.27 (1.07 to 1.94). Geometric mean IC to plasma AUC ratios were 5.3 and 4.9 for darunavir in groups 1 and 2 when darunavir/ritonavir was given alone and 4.9 and 5.6 for raltegravir when given alone. These ratios were not altered by the coadministered drug. CONCLUSIONS:No remarkable interactions between darunavir/ritonavir and raltegravir in plasma or cells were seen. Raltegravir IC concentrations are higher than previously reported; the difference being due to modified cell isolation procedures that reduced drug loss caused by washing.
| S-EPMC3594701 | biostudies-literature
Project description:BackgroundIndacaterol acetate (IND), a long-acting β2-agonist in combination with mometasone furoate (MF), an inhaled corticosteroid (ICS), is being explored as a once-daily (od) treatment for asthma in children. This study examined the efficacy, safety, and systemic exposure of IND 75 µg and IND 150 µg in children with persistent asthma.MethodsIn this Phase IIb, multicenter, randomized, double-blind, parallel-group study, pediatric patients (aged ≥ 6 to < 12 years) with persistent asthma were randomized (1:1) to receive either IND 75 µg od or IND 150 µg od via Breezhaler® in combination with ICS background therapy. The primary endpoint was change from baseline in pre-dose trough forced expiratory volume in one second (FEV1) after two weeks of treatment.ResultsIn total, 80 patients received IND 75 µg (n = 39) or IND 150 µg (n = 41). The study met its primary endpoint; both doses demonstrated improvements in pre-dose trough FEV1 from baseline to Day 14 (mean change [Δ]: 212 mL, IND 75 µg; 171 mL, IND 150 µg). The secondary spirometry parameters (post-dose FEV1 after 1-h, post-dose forced vital capacity; morning and evening peak expiratory flow) also improved. Overall, 36.1% in IND 75 μg group and 25% patients in IND 150 μg group achieved a decrease from baseline in Pediatric Interviewer-administered Asthma Control Questionnaire score of ≥ 0.5 units. A dose-dependent increase in plasma IND concentration was noted between the two groups. Both IND doses demonstrated an acceptable safety profile.ConclusionsOnce-daily IND 75 μg and IND 150 μg via Breezhaler® in combination with background ICS therapy provided substantial bronchodilation in children with asthma and were well tolerated. Taken together, these clinical and systemic exposure findings support IND 75 μg as the most appropriate dose for evaluation in Phase III trials in combination with MF in pediatric asthma.Trial registrationClinicalTrials.gov (NCT02892019; 08-Sep-2016).
| S-EPMC10514176 | biostudies-literature