Using Mixture of Normal Distributions to Detect Treatment Effects when the Frequentist Method Fails

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Anthony Orlando
Keyword(s):  
Dose Response ◽  
Linear Models ◽  
Controlled Trial ◽  
Response To Treatment ◽  
Double Blind ◽  
Underlying Assumption ◽  
Normal Distributions ◽  
Efficacy Measure ◽  
Baseline Weight ◽  
Mixture Of Normal Distributions

Background: Results from a clinical trial can either support the efficacy and safety of a new compound or fail to provide such evidence. One reason for ‘non[1]positive’ result is due to the underlying assumption of normality and homogeneity of variances, which are quite often violated when analyzing data from clinical trials, despite randomization. A question of interest is can we obtain more informative results when using mixture of normal distributions or linear models (MLMs) in such cases. Introduction: MLM can be used when traditional methods fail. MLMs “search” within the variability in data to identify components or subgroups of individuals (also known as latent classes) who have common intercepts and common slopes of change in a variable/endpoint of interest but whose intercepts and slopes are different from other subsets of patients. Thus, MLMs can be used to identify subgroups of patients exhibiting differential response to treatment within each treatment arm. The purpose of our study was to examine the usefulness of using MLM in such circumstances. Methods: Data of 155 subjects taken from a Multicenter, randomized, double blind, placebo controlled trial that evaluated the efficacy of Cpn10, administered twice weekly subcutaneously to treat Rheumatoid Arthritis was taken to evaluate the usefulness of MLM. The primary efficacy measure ACR20 was analyzed using a 3-step process: first, MLM was used to estimate RA duration using a 3-component model. The second step took the results of the first step to inform the logistic model and its analyses. Model was fitted with an intercept, MLM components, treatment arm, RA duration (linear and quadratic), dose response (modeled as an interaction effect), age and baseline weight. LOCF was used to impute for missing data. Data was analyzed using MLM and SAS v 9.0. Results: The model was a good fit to the data with a likelihood ratio significant at p=0.026, and a significant increase in the -2log L. We also observed low p-values for those variables that were non normal. Overall and for the 75 mg dose, Cpn 10 was efficacious relative to placebo, p<0.050. We also observed that dose response was significant at p><0.15 Conclusion: The use of MLM adds value because it can be used to understand the disease experience or the value of treatment when traditional statistical methods cannot. Key words: Mixture of linear models, normality, entropy.

scholarly journals Methotrimeprazine versus haloperidol in palliative care patients with cancer-related nausea: a randomised, double-blind controlled trial

BMJ Open ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. e029942 ◽  
Author(s):  
Janet Rea Hardy ◽  
Helen Skerman ◽  
Jennifer Philip ◽  
Phillip Good ◽  
David C Currow ◽  
...  
Keyword(s):  
Palliative Care ◽  
Outcome Measures ◽  
Controlled Trial ◽  
Response Rates ◽  
Complete Response ◽  
Response To Treatment ◽  
Secondary Outcome ◽  
Double Blind ◽  
Intention To Treat ◽  
Point Reduction

ObjectivesMethotrimeprazine is commonly used for the management of nausea but never tested formally against other drugs used in this setting. The aim was to demonstrate superior antiemetic efficacy.DesignDouble-blind, randomised, controlled trial of methotrimeprazine versus haloperidol.Setting11 palliative care sites in Australia.ParticipantsParticipants were >18 years, had cancer, an average nausea score of ≥3/10 and able to tolerate oral medications. Ineligible patients had acute nausea related to treatment, nausea for which a specific antiemetic was indicated, were about to undergo a procedure or had received either of the study drugs or a change in glucocorticoid dose within the previous 48 hours.InterventionsBased on previous studies, haloperidol was used as the control. Participants were randomised to encapsulated methotrimeprazine 6·25 mg or haloperidol 1·5 mg one time or two times per day and assessed every 24 hours for 72 hours.Main outcome measuresA ≥two-point reduction in nausea score at 72 hours from baseline. Secondary outcome measures were as follows: complete response at 72 hours (end nausea score less than 3), response at 24 and 48 hours, vomiting episodes, use of rescue antiemetics, harms and global impression of change.ResultsResponse to treatment at 72 hours was 75% (44/59) in the haloperidol (H) arm and 63% (36/57) in the methotrimeprazine (M) arm with no difference between groups (intention-to-treat analysis). Complete response rates were 56% (H) and 51% (M). In theper protocolanalysis, there was no difference in response rates: (85% (44/52) (H) and 74% (36/49) (M). Completeper protocolresponse rates were 64% (H) and 59% (M). Toxicity worse than baseline was minimal with a trend towards greater sedation in the methotrimeprazine arm.ConclusionThis study did not demonstrate any difference in response rate between methotrimeprazine and haloperidol in the control of nausea.Trial registration numberACTRN 12615000177550.

scholarly journals Acute Effects of Triiodothyronine on Endothelial Function in Human Subjects

2007 ◽  
Vol 92 (1) ◽  
pp. 250-254 ◽  
Author(s):  
Raffaele Napoli ◽  
Vincenzo Guardasole ◽  
Valentina Angelini ◽  
Emanuela Zarra ◽  
Daniela Terracciano ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Dose Response ◽  
Vascular Reactivity ◽  
Controlled Trial ◽  
University Hospital ◽  
Acute Effects ◽  
Response Curves ◽  
Double Blind ◽  
Low T3 ◽  
Dose Response Curves

Abstract Context: Thyroid hormone regulates several cardiovascular functions, and low T3 levels are frequently associated with cardiovascular diseases. Whether T3 exerts any acute and direct effect on endothelial function in humans is unknown. Objective: Our objective was to clarify whether acute changes in serum T3 concentration affect endothelial function. Design, Setting, and Subjects: Ten healthy subjects (age, 24 ± 1 yr) participated in a double-blind, placebo-controlled trial at a university hospital. Interventions: T3 (or placebo) was infused for 7 h into the brachial artery to raise local T3 to levels observed in moderate hyperthyroidism. Vascular reactivity was tested by intraarterial infusion of vasoactive agents. Main Outcome Measures: We assessed changes in forearm blood flow (FBF) measured by plethysmography. Results: FBF response to the endothelium-dependent vasodilator acetylcholine was enhanced by T3 (P = 0.002 for the interaction between T3 and acetylcholine). The slopes of the dose-response curves were 0.41 ± 0.06 and 0.23 ± 0.04 ml/dl·min/μg in the T3 and placebo study, respectively (P = 0.03). T3 infusion had no effect on the FBF response to sodium nitroprusside. T3 potentiated the vasoconstrictor response to norepinephrine (P = 0.006 for the interaction). Also, the slopes of the dose-response curves were affected by T3 (1.95 ± 0.77 and 3.83 ± 0.35 ml/dl·min/mg in the placebo and T3 study, respectively; P &lt; 0.05). The increase in basal FBF induced by T3 was inhibited by NG-monomethyl-l-arginine. Conclusions: T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrine-induced vasoconstriction. The data may help clarify the vascular impact of the low T3 syndrome and point to potential therapeutic strategies.

Double-Blind, Placebo-Controlled Trial of Reformulated Azelastine Nasal Spray in Patients with Seasonal Allergic Rhinitis

2009 ◽  
Vol 23 (5) ◽  
pp. 512-517 ◽  
Author(s):  
Jonathan A. Bernstein ◽  
Bruce Prenner ◽  
Berrylin J. Ferguson ◽  
Jay Portnoy ◽  
William J. Wheeler ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Nasal Spray ◽  
Dose Response ◽  
Seasonal Allergic Rhinitis ◽  
Nasal Congestion ◽  
Controlled Trial ◽  
Taste Masking ◽  
Comparable Efficacy ◽  
Original Formulation ◽  
Double Blind

Background Azelastine nasal spray is a topical antihistamine with a distinctive taste that may be objectionable to some patients. The primary objectives of this clinical trial were (1) to determine if a reformulated azelastine nasal spray (Astepro) with sucralose as a taste-masking agent provides comparable efficacy to the original formulation (Astelin) and (2) to evaluate dose–response relationships between groups. Methods Eight hundred thirty-five patients with seasonal allergic rhinitis were randomized to six treatment groups: (1) original azelastine nasal spray, 1 spray/nostril b.i.d.; (2) reformulated azelastine, 1 spray/nostril b.i.d.; (3) placebo, 1 spray/nostril b.i.d.; (4) original azelastine nasal spray, 2 sprays/nostril b.i.d., (5) reformulated, 2 sprays/nostril b.i.d.; and (6) placebo, 2 sprays/nostril b.i.d. The primary efficacy variable was the change from baseline to day 14 in total nasal symptom score (TNSS) consisting of runny nose, sneezing, itchy nose, and nasal congestion. Results Original azelastine nasal spray and the reformulated spray produced comparable improvements in the TNSS at both dosages. There was a dose-related difference in TNSS comparing the 1- and 2-spray dosages. The percentage changes from baseline in the TNSS in the 2-sprays/nostril dosage groups were 27.9% (p < 0.001) with the reformulated nasal spray, 23.5% (p < 0.01) with the original formulation, and 15.4% with placebo. The incidence of bitter taste was 7% with the reformulated spray and 8% with the original at the 2-sprays/nostril dosage. Conclusion The results of this study showed efficacy both with original azelastine nasal spray and with the reformulated nasal spray and a clear dose–response difference between the 1- and 2-spray dosages.

Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial

2018 ◽  
Vol 235 ◽  
pp. 236-241 ◽  
Author(s):  
Somaye Arabzadeh ◽  
Elham Hakkikazazi ◽  
Nazila Shahmansouri ◽  
Abbas Tafakhori ◽  
Alireza Ghajar ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Oral Administration ◽  
Controlled Trial ◽  
Response To Treatment ◽  
Major Depressive ◽  
Double Blind

Melphalan-Prednisone-Thalidomide (MP-T) Demonstrates a Significant Survival Advantage in Elderly Patients ≥75 Years with Multiple Myeloma Compared with Melphalan-Prednisone (MP) in a Randomized, Double-Blind, Placebo-Controlled Trial, IFM 01/01.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 75-75 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Philippe Rodon ◽  
Brigitte Pegourie ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Partial Response ◽  
Elderly Patients ◽  
Controlled Trial ◽  
Response To Treatment ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Very Elderly ◽  
Double Blind ◽  
Vte Prophylaxis

Abstract Background: The MP-T combination has become the standard treatment for newly diagnosed MM patients (pts) aged 65 to 75 years (Facon et al; Lancet 2007 [Epub ahead of print]). However, no specific therapeutic recommendation exists for pts ≥75 years regarding the benefit of adding thalidomide to MP. Patients older than 75 years have frequently been excluded from large clinical trials, although they represent more than 20% of MM pts. Methods: The IFM 01-01 trial was initiated in 4/2002. Pts ≥75 years with untreated MM were randomized to receive MP-placebo (M [0.2mg/kg/d] + P [2 mg/kg/d day1–4]) x 12 courses every 6-weeks + placebo) or MP-T (MP + daily thalidomide [100mg/d]). No anti-VTE prophylaxis was given. The primary end-point was overall survival (OS). Secondary end points were progression-free survival (PFS), response to treatment, and toxicity. Trial enrollment was prospectively planned for 258 patients. Two interim analyses were performed after inclusion of 150 and 200 patients. The IFM board decided to stop enrollment after the second interim analysis. Results: In all, 232 pts were randomized and 3 failed to meet inclusion criteria. In all, 229 pts were analyzed (113 MP-T; 116 MP-placebo) with a median age of 78.5 years (36% ≥80years). No differences between the 2 groups for baseline characteristics were observed except for gender (p=0.03). Data were analysed on an intent-to-treat basis. The median follow-up time was 24 months. The median OS time (se) was 45.3 (1.6) months with MP-T vs 27.7 (2.1) months with MP-placebo, the benefit was significant (p=0.03 log-rank test). The median PFS time (se) was 24.1 (2) months with MP-T vs 19 (1.4) months with MP-placebo (p=0.001). Rates of at least partial response, very good partial response and complete response were 62%, 22% and 7% with MP-T vs 31%, 7% and 1% with MP-placebo, respectively (p<0.001). In the MP-T arm, 42% of pts stopped treatment due to toxicity vs 11% in the MP-placebo arm. The major reasons in the MP-T arm were peripheral neuropathy (12/48), neutropenia (7/48), and DVT (7/48). Some toxicities (Grade 2–4) were significantly increased with MP-T: peripheral neuropathy (20% vs 5%), neutropenia (23% vs 9%) depression (7% vs 2%). There were no significative differences in DVT rates for MP-T (6%) vs MP-placebo (4%) or somnolence (6% vs 3%, respectively). After relapse in the MP-placebo arm, 77% of patients received Thalidomide. Survival time after progression was similar in the 2 groups, 9.8 months after MP-placebo and 9.3 months after MP-T. Conclusion: These results confirm the superiority of MP-T over MP for prolonging OS in elderly patients with newly diagnosed MM. The toxicity was acceptable in this very elderly population ≥ 75 years. A new era of progress is opened for these very elderly patients.

scholarly journals Estimation of the dietary requirement for vitamin D in adolescents aged 14–18 y: a dose-response, double-blind, randomized placebo-controlled trial

2016 ◽  
Vol 104 (5) ◽  
pp. 1301-1309 ◽  
Author(s):  
Taryn J Smith ◽  
Laura Tripkovic ◽  
Camilla T Damsgaard ◽  
Christian Mølgaard ◽  
Christian Ritz ◽  
...  
Keyword(s):  
Vitamin D ◽  
Dose Response ◽  
Controlled Trial ◽  
Double Blind ◽  
Dietary Requirement

scholarly journals A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Duliang Soft Capsule in Patients with Chronic Daily Headache

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Shengyuan Yu ◽  
Yueqing Hu ◽  
Qi Wan ◽  
Jiying Zhou ◽  
Xinfeng Liu ◽  
...  
Keyword(s):  
Chronic Daily Headache ◽  
Prophylactic Treatment ◽  
Controlled Trial ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Headache Severity ◽  
Efficacy Measure ◽  
Daily Headache ◽  
Efficacy Measures ◽  
Accompanying Symptoms

Objective. To investigate the efficacy and safety of traditional Chinese medicine Duliang soft capsule (DSC) in prophylactic treatment for patients with chronic daily headache (CDH). Methods. A multicenter, double-blind, randomized, placebo-controlled clinical study was conducted at 18 Chinese clinical centers. The participants received either DSC or placebo for 4 weeks. The primary efficacy measure was headache-free rate (HFR) in a 4-week period between the pretreatment and posttreatment stages. The secondary efficacy measures were the decrease of headache days, the duration of headache attacks, the frequency of analgesic usage, quality of life, disability, and the headache severity (VAS scores). The accompanying symptoms and adverse events were also assessed. Results. Of 584 CDH patients assessed, 468 eligible patients were randomized. 338 patients received DSC, while 111 patients were assigned in the placebo group. Following treatment, there was a 16.56% difference in HFR favoring DSC over placebo (P<0.01). Significant differences were also observed between DSC and placebo groups in the secondary measures. However, no statistical difference was found between the two groups in the associated symptoms. No severe adverse effects were observed in the study. Conclusions. DSC might be an effective and well-tolerated option for the prophylactic treatment of patients with CDH.

Pharmacodynamics and Dose-Response Relationship of Famotidine: A Double-Blind Randomized Placebo-Controlled Trial

1993 ◽  
Vol 33 (7) ◽  
pp. 636-639 ◽  
Author(s):  
Oscar L. Laskin ◽  
Patricia M. Patterson ◽  
Sumiko Shingo ◽  
Kenneth C. Lasseter ◽  
E. Cooper Shamblen
Keyword(s):  
Dose Response ◽  
Controlled Trial ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Double Blind ◽  
Relationship Of

scholarly journals Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: Randomised double-blind placebo-controlled trial

2016 ◽  
Vol 208 (1) ◽  
pp. 78-86 ◽  
Author(s):  
Lakshmi N. Yatham ◽  
Eduard Vieta ◽  
Guy M. Goodwin ◽  
Michel Bourin ◽  
Christian de Bodinat ◽  
...  
Keyword(s):  
Adjunctive Therapy ◽  
Rating Scale ◽  
Bipolar Depression ◽  
Controlled Trial ◽  
Acute Therapy ◽  
Double Blind ◽  
Continuation Therapy ◽  
Primary Efficacy Measure ◽  
Scale Scores ◽  
Efficacy Measure

BackgroundAdjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy.AimsTo examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression.MethodPatients who were currently depressed despite taking lithium or valproate for at least 6 weeks were randomised to treatment with agomelatine (n = 172) or placebo (n = 172) for 8 weeks of acute therapy and 44 weeks of continuation therapy (trial registration: ISRCTN28588282).ResultsNo significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery–Åsberg Depression Rating Scale scores from baseline to end-point. Adverse events including switches into mania/hypomania were low and similar in both groups.ConclusionsAgomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression.

Agomelatine in the treatment of obsesive-compulsive-disorder: Potential for clinical effectiveness: An 4-week, multicenter, randomized, placebo-controlled trial

2011 ◽  
Vol 26 (S2) ◽  
pp. 974-974 ◽  
Author(s):  
P. Marqués Cabezas ◽  
G. Cabus Piñol ◽  
J. Coullaut-Valera García ◽  
C. Dominguez Martín ◽  
J.L. Villegas Martinez
Keyword(s):  
Clinical Response ◽  
Rating Scale ◽  
Controlled Trial ◽  
Clinical Effectiveness ◽  
Fixed Dose ◽  
Obsessive Compulsive ◽  
Double Blind ◽  
Compulsive Disorder ◽  
Significant Difference ◽  
Efficacy Measure

ObjectiveTo evaluate the efficacy, safety, and tolerability of fixed-dose agomelatine 25 and 50 mg/d in the treatment of outpatients with obsesive-compulsive disorder (OCD) compared to placebo.MethodIn this 8-week, multicenter, double-blind, parallel-group trial, patients with DSM-IV-defined OCD were randomly assigned (1:1:1) to receive a once-daily dose of agomelatine 25 mg, agomelatine 50 mg, or placebo. The primary efficacy measure was the change from baseline to week 8 in the clinician-rated 17-item Hamilton Depression Rating Scale (HDRS(17)); other efficacy measures were The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Clinical Global Impression scale. The study was conducted between December 2009 and January 2010.ResultsAgomelatine 25 mg/d was more efficacious based on the HDRS(17) total score (P = .01) compared to placebo throughout the treatment period, whereas for agomelatine 50 mg/d, statistically significant reduction in HDRS(17) total score could be observed from weeks 2 to 6 but not at week 8 (P = .144). A higher proportion of patients receiving agomelatine 25 mg/d showed clinical response (P = .013), clinical remission (P = .07), and improvement according to the Clinical Global Impressions-Improvement scale (P = .065) compared to those receiving placebo. No statistically significant difference between patients receiving agomelatine 50 mg/d compared to placebo on clinical response. Both agomelatine doses were safe and well tolerated, although clinically notable aminotransferase elevations were observed transiently in the agomelatine 50 mg/d group.ConclusionsAgomelatine 50 mg/d provided evidence for its antidepressant efficacy until week 6 and was also safe and well tolerated.

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