Post hoc analysis of a randomised, placebo-controlled, active-reference 6-week study of brexpiprazole in acute schizophrenia

AbstractObjective:We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint – change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.Methods:Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.Results:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: −4.3 [95% CI (−8.0, −0.5), p = 0.0254]. OC, ANCOVA: −3.9 [95% CI (−7.3, −0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of −29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of −13.5 [95% CI (−23.1, −4.0), p = 0.0057], and those who did not had an LS mean change of −18.9 and a difference between brexpiprazole and placebo of −2.9 [95% CI (−7.2, 1.4), p = 0.1809].Conclusion:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.

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Changes in respiratory symptoms during 48-week treatment with ARD-3150 (inhaled liposomal ciprofloxacin) in bronchiectasis: results from the ORBIT-3 and -4 studies

European Respiratory Journal ◽

10.1183/13993003.00110-2020 ◽

2020 ◽

Vol 56 (4) ◽

pp. 2000110

Author(s):

James D. Chalmers ◽

David Cipolla ◽

Bruce Thompson ◽

Angela M. Davis ◽

Anne O'Donnell ◽

...

Keyword(s):

Repeated Measures ◽

Respiratory Symptoms ◽

Mixed Model ◽

Bacterial Load ◽

Minimum Clinically Important Difference ◽

Symptom Improvement ◽

Symptom Scale ◽

Inhaled Antibiotics ◽

Post Hoc ◽

Relationship Of

It is not known if inhaled antibiotics improve respiratory symptoms in patients with bronchiectasis. In the recent phase-3 ORBIT trials, 48 weeks' treatment with ARD-3150 (inhaled liposomal ciprofloxacin) did not significantly improve symptoms using the prespecified method of analysis comparing baseline symptoms to those after 48 weeks, when patients had been off treatment for 28 days. This method of analysis does not take account of possible improvements in symptoms while on active treatment.A post hoc analysis of two identical randomised trials of ARD-3150 (ORBIT-3 and -4) administered 28 days on and 28 days off in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. The quality-of-life bronchiectasis respiratory symptom scale (QOL-B-RSS), which has a one-week recall period, was administered every 28 days. We examined whether respiratory symptoms improved during on-treatment periods and the relationship of changes in QOL-B-RSS to changes in bacterial load using a mixed-model repeated measures approach.ARD-3150 treatment resulted in a significant improvement in respiratory symptoms during the on-treatment periods with concordant results between ORBIT-3 (estimate 1.4 points, se 0.49; p=0.004) and ORBIT-4 (estimate 1.1 point, se 0.41; p=0.006). The proportion of patients achieving a symptom improvement above the minimum clinically important difference was higher with ARD-3150 compared with placebo during on-treatment cycles (p=0.024). Changes in respiratory symptoms were correlated with changes in bacterial load in the treatment group (r=−0.89, p<0.0001). Individual estimates for decrements in the QOL-B RSS during exacerbation were −9.4 points (se 0.91) in ORBIT-3 and −10.8 points (0.74) in ORBIT-4 (both p<0.0001).Inhaled ARD-3150 resulted in significant improvements in respiratory symptoms during the on-treatment periods which were lost during off-treatment periods. These results supports the concept that reducing bacterial load can improve respiratory symptoms in patients with bronchiectasis.

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Efficacy of galcanezumab in patients with migraine who did not benefit from commonly prescribed preventive treatments

BMC Neurology ◽

10.1186/s12883-021-02196-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dulanji K. Kuruppu ◽

Joshua Tobin ◽

Yan Dong ◽

Sheena K. Aurora ◽

Laura Yunes-Medina ◽

...

Keyword(s):

Repeated Measures ◽

Migraine Headache ◽

Mixed Model ◽

Preventive Treatment ◽

Response Rates ◽

Toxin A ◽

Double Blind ◽

Preventive Medication ◽

Onabotulinum Toxin A ◽

Post Hoc

Abstract Background Galcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown. Methods CONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1–3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures. Results The most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1–3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1–3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01). Conclusions In this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability. Trial registration ClinicalTrials.gov NCT03559257 (CONQUER).

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The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors

European Psychiatry ◽

10.1016/j.eurpsy.2019.01.015 ◽

2019 ◽

Vol 58 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Wolfgang Fleischhacker ◽

Silvana Galderisi ◽

István Laszlovszky ◽

Balázs Szatmári ◽

Ágota Barabássy ◽

...

Keyword(s):

Negative Symptom ◽

Repeated Measures ◽

Negative Symptoms ◽

Social Withdrawal ◽

Partial Agonist ◽

Factor Models ◽

Symptom Improvement ◽

Symptom Dimensions ◽

Intent To Treat ◽

Post Hoc

AbstractBackground:Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms.Methods:Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227).Results:Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P <.05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P <.01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P <.05).Conclusions:Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.

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Comparison of music stimuli to support mindfulness meditation

Psychology of Music ◽

10.1177/0305735619878497 ◽

2019 ◽

pp. 030573561987849 ◽

Cited By ~ 3

Author(s):

Abbey L Dvorak ◽

Eugenia Hernandez-Ruiz

Keyword(s):

Repeated Measures ◽

Mindfulness Meditation ◽

Analysis Of Covariance ◽

Auditory Stimuli ◽

Harmonic Progression ◽

Repeated Measures Design ◽

Significant Difference ◽

Within Subjects ◽

Mindful Attention Awareness Scale ◽

Post Hoc

The purpose of this study was to compare the effectiveness of and preference for different auditory stimuli in supporting mindfulness meditation. Undergraduate non-musicians ( N = 57) listened to four different auditory stimuli guiding them in a mindfulness meditation: script only (i.e., Script), steady beat (i.e., Beat), beat and harmonic progression (i.e., Harmony), and beat, harmony, and melody (i.e., Melody). This study used a within-subjects repeated-measures design with the four conditions counterbalanced and randomized across participants. Participants rated responses using the Mindful Attention Awareness Scale (MAAS), completed the Absorption in Music Scale (AIMS), and ranked auditory stimuli according to preference and usefulness for mindfulness meditation. A repeated-measures analysis of covariance (ANCOVA) on the MAAS scores, using the AIMS as a covariate, indicated no statistically significant difference between auditory stimuli. However, with the AIMS removed, the analysis revealed significant differences between stimuli, indicating that levels of absorption in music may moderate participants’ responses to auditory stimuli for mindfulness meditation. Friedman analyses of variance (ANOVAs) and post hoc analyses indicated that participant rankings of usefulness and preference were significantly different among conditions, with the Melody and Harmony conditions ranked highest.

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Abstract 52: Efficacy and Safety of Mipomersen in Patients with Familial Hypercholesterolemia and Inadequately Controlled LDL-C Levels

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.52 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Christie Ballantyne ◽

Alberico L Catapano ◽

Michael Davidson ◽

Robert Mittleman ◽

Patrick M Moriarty ◽

...

Keyword(s):

Adverse Events ◽

Familial Hypercholesterolemia ◽

Repeated Measures ◽

Mixed Model ◽

Primary Objective ◽

Tolerability Profile ◽

Primary Analysis ◽

Double Blind ◽

Absolute Reduction ◽

Over Time

Aim: Mipomersen is an antisense oligonucleotide inhibitor of apolipoprotein B-100 synthesis, FDA-approved to treat homozygous familial hypercholesterolemia. The primary objective of this study was to determine whether mipomersen significantly reduced atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (HeFH). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study comprised of two cohorts (NCT01475825). Cohort 1 had severe HeFH (LDL-C ≥200 mg/dL + coronary heart disease, or LDL-C ≥300 mg/dL) and Cohort 2 had milder HeFH (LDL-C ≥160 and <200 mg/dL). For each cohort, patients were randomized 1:1 to 200 mg SC once weekly or 70 mg SC thrice weekly, then 2:1 to receive mipomersen or placebo for 60 weeks. The primary outcome was percent change from baseline in LDL-C in Cohort 1. The % change from baseline in LDL-C at Week 61 for mipomersen treated patients was compared to placebo using a mixed model for repeated measures (MMRM), as well as by ANCOVA on the value closest to 7 days post last treatment (LOCF). Results: Mean baseline LDL-C levels were 265 mg/dL in Cohort 1 (N=200) and 176 mg/dL in Cohort 2 (N=109). In Cohort 1, mipomersen 200 mg weekly reduced LDL-C levels by -29.7% (vs -7.9% placebo, P <.001) in the mixed model, and by -36.3% (vs -7.6% placebo, P <.001) using the LOCF. Analysis of LDL-C over time (Figure) showed a mean absolute reduction of 138 mg/dL in mipomersen patients who completed the blinded treatment period (n=32), achieving a mean level of 147 mg/dL from a mean 285 mg/dL baseline level. Tolerability to treatment and adverse events were similar between dose regimens. Adverse events were consistent with the drug’s known safety and tolerability profile. Conclusions: The primary analysis showed a significant reduction in LDL-C levels in patients with severe HeFH who received mipomersen 200 mg once weekly versus placebo. A highly relevant absolute reduction in LDL-C was achieved over time.

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Utility of the Actiheart Accelerometer for Estimating Exercise Energy Expenditure in Female Adolescent Runners

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.20.6.487 ◽

2010 ◽

Vol 20 (6) ◽

pp. 487-495 ◽

Cited By ~ 7

Author(s):

Jeanne F. Nichols ◽

Hilary Aralis ◽

Sonia Garcia Merino ◽

Michelle T. Barrack ◽

Lindsay Stalker-Fader ◽

...

Keyword(s):

Heart Rate ◽

Energy Expenditure ◽

Repeated Measures ◽

Mixed Model ◽

Linear Mixed Model ◽

Young Female ◽

Female Adolescent ◽

Treadmill Running ◽

Exercise Energy Expenditure ◽

Post Hoc

There is a growing need to accurately assess exercise energy expenditure (EEE) in athletic populations that may be at risk for health disorders because of an imbalance between energy intake and energy expenditure. The Actiheart combines heart rate and uniaxial accelerometry to estimate energy expenditure above rest. The authors’ purpose was to determine the utility of the Actiheart for predicting EEE in female adolescent runners (N = 39, age 15.7 ± 1.1 yr). EEE was measured by indirect calorimetry and predicted by the Actiheart during three 8-min stages of treadmill running at individualized velocities corresponding to each runner’s training, including recovery, tempo, and 5-km-race pace. Repeated-measures ANOVA with Bonferroni post hoc comparisons across the 3 running stages indicated that the Actiheart was sensitive to changes in intensity (p < .01), but accelerometer output tended to plateau at race pace. Pairwise comparisons of the mean difference between Actiheart- and criterion-measured EEE yielded values of 0.0436, 0.0539, and 0.0753 kcal · kg−1 · min−1 during recovery, tempo, and race pace, respectively (p < .0001). Bland–Altman plots indicated that the Actiheart consistently underestimated EEE except in 1 runner’s recovery bout. A linear mixed-model regression analysis with height as a covariate provided an improved EEE prediction model, with the overall standard error of the estimate for the 3 speeds reduced to 0.0101 kcal · kg−1 · min−1. Using the manufacturer’s equation that combines heart rate and uniaxial motion, the Actiheart may have limited use in accurately assessing EEE, and therefore energy availability, in young, female competitive runners.

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Oxytocin and Oxytocinase in the Obese and Nonobese Parturients during Induction and Augmentation of Labor

American Journal of Perinatology Reports ◽

10.1055/s-0039-1692196 ◽

2019 ◽

Vol 09 (02) ◽

pp. e177-e184

Author(s):

Annemaria De Tina ◽

Jeremy Juang ◽

Thomas F. McElrath ◽

Jack D. Baty ◽

Arvind Palanisamy

Keyword(s):

Repeated Measures ◽

Mixed Model ◽

Group Versus ◽

Preliminary Evidence ◽

Analysis Of Covariance ◽

Uterine Contractions ◽

Time Interaction ◽

Repeated Measures Analysis ◽

Elective Induction ◽

The Mean

Objective To investigate differences in oxytocin (OXT) biodistribution between nonobese and obese parturients during labor. Study Design Patients with body mass index (BMI) of either ≥ 18 ≤ 24.9 kg/m2 (“nonobese”) or ≥ 30 kg/m2 (“obese”) undergoing elective induction of labor were included (N = 25 each). Blood samples were collected at baseline (T0), and 20 minutes after maximal OXT augmentation or adequate uterine contractions (T1) for OXT and oxytocinase assays. A mixed-model repeated-measures analysis of variance was used to test for group versus time interaction and analysis of covariance to detect a difference in OXT level at T1. Data presented as mean ± standard deviation or median (interquartile range), with p < 0.05 considered significant. Results The mean BMIs (kg/m2) were 22.1 ± 1.6 and 35.9 ± 5.1 in the nonobese and obese groups, respectively. No differences were observed in either the duration of OXT infusion, total dose of OXT, or plasma OXT (pg/mL) either at T0 or T1. However, plasma oxytocinase (ng/mL) was significantly lower at T0 (1.41 [0.67, 3.51] vs. 0.40 [0.29, 1.12]; p = 0.03) in the obese group. Conclusion We provide preliminary evidence that the disposition of OXT may not be different between obese and nonobese women during labor.

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Home-based Pilates for symptoms of anxiety, depression and fatigue among persons with multiple sclerosis: An 8-week randomized controlled trial

Multiple Sclerosis Journal ◽

10.1177/13524585211009216 ◽

2021 ◽

pp. 135245852110092

Author(s):

Karl M Fleming ◽

Susan B Coote ◽

Matthew P Herring

Keyword(s):

Multiple Sclerosis ◽

Repeated Measures ◽

Depressive Symptomatology ◽

Depression Scale ◽

Analysis Of Covariance ◽

Sensitivity Analyses ◽

Anxiety And Depression ◽

Hospital Anxiety ◽

Home Based ◽

Anxiety Depression

Background: Symptoms of anxiety, depression and fatigue are common comorbidities among persons with multiple sclerosis (PwMS). A previous pilot study supported Pilates as a feasible exercise modality that may improve these outcomes among PwMS. Objective: To quantify the effects of 8 weeks of home-based Pilates on symptoms of anxiety, depression and fatigue among PwMS. Methods: A total of 80 PwMS (69 female) were randomized to twice-weekly home-based Pilates guided by a DVD) or wait-list control. Validated questionnaires assessed anxiety, depressive and fatigue symptoms at baseline, weeks 2, 4, 6 and 8. Using intention to treat, repeated measures analysis of covariance (RM-ANCOVA) adjusted for baseline physical activity examined between-group differences across time. Hedges’ d quantified the magnitude of differences in outcome change. Sensitivity analyses examined female-only samples. Results: Group × time interactions were statistically significant for all outcomes (all p ⩽ 0.005). Pilates significantly reduced (all p ⩽ 0.03) depressive symptoms (Quick Inventory of Depressive Symptomatology, d = 0.70; Hospital Anxiety and Depression Scale-Depression, d = 0.74), anxiety (State-Trait Anxiety Inventory, d = 0.30; Hospital Anxiety and Depression Scale-Anxiety, d = 0.49), cognitive ( d = 0.44), physical ( d = 0.78), psychosocial ( d = 0.56) and total fatigue ( d = 0.76). Female-only results were materially the same. Conclusion: Home-based Pilates significantly improved anxiety, depressive and fatigue symptoms among PwMS with minimal-to-mild mobility disability, including moderate-to-large, clinically meaningful improvements in depressive and fatigue symptoms. Trial Registration: ClinicalTrials.gov (NCT04120207)

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Sustained, Multifaceted Improvements in Mental Well-Being Following Psychedelic Experiences in a Prospective Opportunity Sample

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.647909 ◽

2021 ◽

Vol 12 ◽

Author(s):

Keri Mans ◽

Hannes Kettner ◽

David Erritzoe ◽

Eline C. H. M. Haijen ◽

Mendel Kaelen ◽

...

Keyword(s):

Repeated Measures ◽

Mixed Model ◽

Positive Impact ◽

Well Being ◽

Policy Implications ◽

Attrition Rates ◽

Before And After ◽

Post Hoc ◽

Prior Intention ◽

Mental Well Being

In the last 15 years, psychedelic substances, such as LSD and psilocybin, have regained legitimacy in clinical research. In the general population as well as across various psychiatric populations, mental well-being has been found to significantly improve after a psychedelic experience. Mental well-being has large socioeconomic relevance, but it is a complex, multifaceted construct. In this naturalistic observational study, a comprehensive approach was taken to assessing well-being before and after a taking a psychedelic compound to induce a “psychedelic experience.” Fourteen measures of well-being related constructs were included in order to examine the breadth and specificity of change in well-being. This change was then analysed to examine clusters of measures changing together. Survey data was collected from volunteers that intended to take a psychedelic. Four key time points were analysed: 1 week before and 2 weeks, 4 weeks, and 2 years after the experience (N = 654, N = 315, N = 212, and N = 64, respectively). Change on the included measures was found to cluster into three factors which we labelled: 1) “Being well”, 2) “Staying well,” and 3) “Spirituality.” Repeated Measures Multivariate Analysis of Variance revealed all but the spirituality factor to be improved in the weeks following the psychedelic experience. Additional Mixed model analyses revealed selective increases in Being Well and Staying Well (but not Spirituality) that remained statistically significant up to 2 years post-experience, albeit with high attrition rates. Post-hoc examination suggested that attrition was not due to differential acute experiences or mental-health changes in those who dropped out vs. those who did not. These findings suggest that psychedelics can have a broad, robust and sustained positive impact on mental well-being in those that have a prior intention to use a psychedelic compound. Public policy implications are discussed.

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Efficacy of Dulaglutide Expanded Doses by Baseline A1C Categories: Post Hoc Analysis of AWARD-11

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.678 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A332-A333

Author(s):

Juan Pablo Frias ◽

Enzo Bonora ◽

David A Cox ◽

Anita Kwan ◽

Sohini Raha ◽

...

Keyword(s):

Glycemic Control ◽

Adverse Events ◽

Dose Escalation ◽

Repeated Measures ◽

Post Hoc Analysis ◽

Metformin Monotherapy ◽

Lower Baseline ◽

The Difference ◽

Glycemic Target ◽

Post Hoc

Abstract The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide (DU) once weekly doses of 3 mg and 4.5 mg compared to DU 1.5 mg in patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. This exploratory post hoc analysis of AWARD-11 assessed the effect of dulaglutide on A1C reduction by clinically-relevant baseline A1C subgroups (<8%; 8%-<9%; 9%-<10%; ≥10%) and the proportion of patients achieving A1C <7% in these subgroups through 36 and 52 weeks. Patients were randomized to once weekly DU 1.5 mg (n=612), 3 mg (n=616), or 4.5 mg (n=614). All patients initiated once weekly DU 0.75 mg for 4 weeks, followed by stepwise dose escalation every 4 weeks to the randomized dose. A mixed effects model for repeated measures was used within the A1C subgroups to assess the change in A1C from baseline at 36 and 52 weeks. A longitudinal logistic regression model was used within subgroups to analyze the proportion of patients achieving A1C <7% at 36 and 52 weeks. Efficacy analyses used data collected up to initiation of rescue medication or premature treatment discontinuation, if either occurred. DU 1.5 mg reduced A1C across all baseline A1C categories at 36 weeks (range, -1.0 to -2.2%) and effects were sustained through 52 weeks (range, -1.0 to -2.1%). A1C reductions were greater in patients randomized to DU 3 mg or 4.5 mg versus 1.5 mg in each A1C subgroup, with greater dose-related improvements in patients with higher baseline A1C through 36 weeks (A1C subgroup, least-squares mean change in A1C [%] with 1.5 mg, 3 mg, and 4.5 mg, respectively: A1C<8%, -1.0, -1.2, -1.2; A1C 8-<9%, -1.4, -1.6, -1.8; A1C 9-<10%, -2.1, -2.2, -2.3; A1C ≥10%, -2.2, -2.5, -3.2; interaction p<0.001). More patients randomized to 3 mg or 4.5 mg achieved A1C <7% versus those on 1.5 mg at 36 weeks regardless of baseline A1C, but the difference across dose groups was greater at higher baseline A1Cs. Over half of patients randomized to DU 4.5 mg achieved A1C <7% in every baseline A1C category (A1C<8%, 75%, 87%, 83%; A1C 8-<9%, 61%, 64%, 73%; A1C 9-<10%, 46%, 51%, 64%; A1C ≥10%, 19%, 33%, 55% for DU 1.5 mg, 3 mg, and 4.5 mg, respectively; interaction p=0.096). Similar patterns of dose-related improvement in A1C and proportions of patients achieving A1C <7% across baseline A1C categories were observed at 52 weeks. Gastrointestinal adverse events were similar between A1C subgroups. Glycemic control as measured by A1C and proportion of patients achieving A1C <7% was improved with DU dose escalation from 1.5 mg to 3 mg or 4.5 mg across a spectrum of clinically relevant baseline A1C categories without increasing incidence of GI adverse events. Patients at higher baseline A1Cs (9%-<10% and ≥10%) had larger dose-related improvements in glycemic control than those at lower baseline A1Cs (<8% and 8%-<9%). The majority of patients randomized to DU 4.5 mg achieved glycemic target across all categories of baseline A1C.

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