Clinically Relevant Outcomes Based on Analysis of Pooled Data from 2 Trials of Duloxetine in Patients with Knee Osteoarthritis

Objective.To determine response with duloxetine versus placebo in patients with osteoarthritis (OA) of the knee using the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responder index and other clinically relevant outcomes including minimal clinically important improvement (MCII) and patient acceptable symptom state (PASS) for pain and function.Methods.Data were pooled from two 13-week, randomized, double-blind, placebo-controlled trials comparing duloxetine 60 to 120 mg/day with placebo in patients with symptomatic OA of the knee. Treatment response was determined according to the OMERACT-OARSI responder index, ≥ 30% pain reduction, ≥ 50% pain reduction, and MCII and PASS for pain and function. (ClinicalTrials.gov identifiers NCT00433290 and NCT00408421)Results.Duloxetine-treated patients were 33% more likely to experience an OMERACT-OARSI response than placebo-treated patients [p < 0.001, number needed to treat (NNT) = 6]. A significantly greater percentage of duloxetine-treated patients, compared with placebo-treated patients, reported ≥ 30% improvement in pain from baseline to endpoint (p < 0.001, NNT = 5) and ≥ 50% improvement in pain relative to baseline (p < 0.001, NNT = 7). The duloxetine-treated patients were also more likely to fulfill MCII criteria for pain (p < 0.001, NNT = 6) and function (p < 0.001, NNT = 7), and to achieve PASS for pain (p < 0.001, NNT = 6) and function (p = 0.009, NNT = 9). More duloxetine-treated patients compared with placebo-treated patients experienced ≥ 1 treatment-emergent adverse event (p = 0.003, number needed to harm = 8).Conclusion.Significantly more patients receiving duloxetine than placebo achieved an OMERACT-OARSI response, improvements in pain and function exceeding the level accepted as MCII, and reached PASS. Results support the clinical relevance of outcomes of prior duloxetine studies in symptomatic OA of the knee.

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Is it Worth CANVASing for CREDENCE? A Benefit-risk Analysis

Current Diabetes Reviews ◽

10.2174/1573399815666191025094733 ◽

2020 ◽

Vol 16 (5) ◽

pp. 509-514

Author(s):

Binayak Sinha ◽

Samit Ghosal

Keyword(s):

Adverse Events ◽

Fungal Infections ◽

Absolute Risk ◽

Pooled Analysis ◽

Major Adverse Cardiovascular Events ◽

Number Needed To Treat ◽

Pooled Data ◽

The Individual ◽

Fracture Risks ◽

Number Needed To Harm

Background and Aims: A number of significant positive and negative signals emerged from the CANVAS Program and CREDENCE trial with the use of canagliflozin. These signals are confusing. A Likelihood of being Helped of Harmed (LHH) analysis was conducted to determine the risk, benefit ratio associated with canagliflozin use and address the signals as a continuum. Materials &Methods: LHH was calculated from the number needed to treat (NNT) and number needed to harm (NNH) available from the absolute risk reductions reported with the outcomes of interest, in these two trials. Results: In the CANVAS Program, LHH for major adverse cardiovascular events (MACE) points at a significant benefit with canagliflozin use in comparison to amputation (1.65), fractures (1.65) and euglycaemic diabetic ketoacidosis (euDKA) (16.67) risks. Only genital fungal infections were significant more in both sexes (0.21-M and 0.1-F) when LHH was matched against the positive outcomes. In contrast, the hHF benefits were outweighed by amputation (0.95) and fracture risks (0.95). : In CREDENCE trial, the LHH for Primary composite, Renal composite and MACE, all supported the benefits in comparison to any adverse events encountered in the trial. : The LHH from pooled data (CANVAS Program and CREDENCE trial) was in favour of all the benefits (hHF and renal composites) except for MACE matched against amputation (0.66). Conclusion: The outcome benefits were in favour of canagliflozin in comparison to all reported adverse events, when hHF and renal composite were under consideration, in both the individual and pooled LHH analysis. However, the MACE benefits were overwhelmed by amputation risk in the pooled analysis.

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Prevention of severe COVID-19 in the elderly by early high-titer plasma

10.1101/2020.11.20.20234013 ◽

2020 ◽

Cited By ~ 1

Author(s):

Romina Libster ◽

Gonzalo Pérez Marc ◽

Diego Wappner ◽

Silvina Coviello ◽

Alejandra Bianchi ◽

...

Keyword(s):

Respiratory Disease ◽

Primary Endpoint ◽

High Titer ◽

Controlled Trial ◽

The Elderly ◽

Elderly Subjects ◽

Number Needed To Treat ◽

Double Blind ◽

Access To Treatment ◽

Link Type

AbstractBackgroundTherapies to interrupt progression of early COVID-19 remain elusive. Among them, convalescent plasma in hospitalized patients was unsuccessful, perhaps because antibody should be administered earlier. We advanced plasma infusions to the first 72 hours of symptoms to arrest COVID-19 progression.MethodsA randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV2 in elderly subjects within 72 hours of mild COVID-19 symptoms. The primary endpoint was severe respiratory disease defined as a respiratory rate ≥30 and/or an O2 sat<93% in room air. The study was interrupted at 76% of its projected sample size, because cases in the region decreased considerably and steady enrollment of study subjects became virtually impossible.Results160 patients underwent randomization. In the intention-to-treat analysis (ITT), 13/80(16.2%) patients receiving plasma vs. 25/80(31.2%) receiving placebo experienced severe respiratory disease [RR(95%CI)= 0.52(0.29,0.94); p=0.026)] with an RRR=48%.A modified ITT analysis, excluding six subjects who experienced the primary endpoint before infusion, showed a larger effect size [RR(95%CI) = 0.40(0.20, 0.81), p=0.007]. High- and low-titer donor analyses, based on a median IgG titer=1:3,200, evidenced a dose-dependent response with an RRR=73.3% for recipients of high-titer plasma (p=0.016) and a number needed to treat (NNT)=4.4. All secondary endpoints exhibited trends towards protection. No solicited adverse events were observed.ConclusionsEarly administration of high-titer convalescent plasma against SARS-CoV2 to mildly ill infected seniors reduced COVID-19 progression. This safe, inexpensive, outpatient intervention facilitates access to treatment from industrialized to LMIC, can decompress demands on hospitals, and may contribute to save lives.Funded by The Bill & Melinda Gates Foundation and The Fundación INFANT Pandemic Fund. Registered in the Dirección de Sangre y Medicina Transfusional del Ministerio de Salud (PAEPCC19), Plataforma PRIISA (1421), and clinicaltrials.gov (NCT04479163).All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; RL, GPM, DW and FPP are investigators in a phase 3 SARS CoV2 trial from Pfizer; no other relationships or activities that could appear to have influenced the submitted work.

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152 Pimavanserin for the Treatment of Parkinson’s Disease Psychosis: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed

CNS Spectrums ◽

10.1017/s1092852918000469 ◽

2018 ◽

Vol 23 (1) ◽

pp. 94-95

Author(s):

Leslie Citrome ◽

James Norton ◽

Kathy Chi-Burris ◽

George Demos

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Adverse Event ◽

Clinical Response ◽

Fixed Dose ◽

Number Needed To Treat ◽

Double Blind ◽

Term Care ◽

Study Objective ◽

Number Needed To Harm

AbstractStudy ObjectivePsychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.MethodsNNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.ResultsNNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are <10, and as robust as 4, denoting that PIM is a potentially efficacious intervention. NNH values for tolerability outcomes for PIM 34 mg/d (as well as for doses that range from 8.5 mg/d to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.ConclusionsUsing the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.

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A Double-Blind Randomized Placebo-Controlled Feasibility Study Evaluating Individualized Homeopathy in Managing Pain of Knee Osteoarthritis

Journal of Evidence-Based Complementary & Alternative Medicine ◽

10.1177/2156587214568668 ◽

2015 ◽

Vol 20 (3) ◽

pp. 186-191 ◽

Cited By ~ 4

Author(s):

Munmun Koley ◽

Subhranil Saha ◽

Shubhamoy Ghosh

Keyword(s):

Knee Osteoarthritis ◽

Research Society ◽

Group Differences ◽

Loss Of Function ◽

Double Blind ◽

Rigorous Evaluation ◽

Medical College ◽

Visual Analog Scales ◽

Osteoarthritis Research Society ◽

Clinical Trials Registry

Few homeopathic complexes seemed to produce significant effects in osteoarthritis; still, individualized homeopathy remained untested. We evaluated the feasibility of conducting an efficacy trial of individualized homeopathy in osteoarthritis. A prospective, parallel-arm, double-blind, randomized, placebo-controlled pilot study was conducted from January to October 2014 involving 60 patients (homeopathy, n = 30; placebo, n = 30) who were suffering from acute painful episodes of knee osteoarthritis and visiting the outpatient clinic of Mahesh Bhattacharyya Homeopathic Medical College and Hospital, West Bengal, India. Statistically significant reduction was achieved in 3 visual analog scales (measuring pain, stiffness, and loss of function) and Osteoarthritis Research Society International scores in both groups over 2 weeks ( P < .05); however, group differences were not significant ( P > .05). Overall, homeopathy did not appear to be superior to placebo; still, further rigorous evaluation in this design involving a larger sample size seems feasible in future. Trial registration: Clinical Trials Registry, India (CTRI/2014/05/004589).

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The Inverse OARSI-OMERACT Criteria Is a Valid Indicator of the Clinical Worsening of Knee Osteoarthritis: Data from the Osteoarthritis Initiative

The Journal of Rheumatology ◽

10.3899/jrheum.200145 ◽

2020 ◽

pp. jrheum.200145

Author(s):

Jeffrey B. Driban ◽

Matthew S. Harkey ◽

Lori Lyn Price ◽

Grace H. Lo ◽

Timothy E. McAlindon

Keyword(s):

Knee Osteoarthritis ◽

Knee Pain ◽

Knee Replacement ◽

Walking Speed ◽

Cox Model ◽

Research Society ◽

Osteoarthritis Initiative ◽

Osteoarthritis Research Society ◽

And Function ◽

Relationship Of

Objective We assessed if the inverse Osteoarthritis Research Society International (OARSI) and Outcome Measures in Rheumatology (OMERACT) criteria relate to concurrent radiographic knee osteoarthritis (KOA) progression and decline in walking speed, as well as future knee replacement. Methods We conducted knee-based analyses of data from the Osteoarthritis Initiative. All knees had symptomatic OA: at least doubtful radiographic KOA (Kellgren-Lawrence grade ≥ 1) and knee pain ≥ 10/100 (Western Ontario and McMaster Universities Osteoarthritis Index pain) at the 12-month visit. The inverse of the OARSI-OMERACT responder criteria depended on knee pain and function, and global assessment of knee impact. We used generalized linear mixed models to assess the relationship of the inverse OARSI‑OMERACT criteria over 2 years (i.e., 12-month and 36-month visits) with worsening radiographic severity (any increase in Kellgren-Lawrence grade from 12 months to 36 months) and decline in self-selected 20-m walking speed of ≥ 0.1m/s (from 12 months to 36 months). We used a Cox model to assess time to knee replacement during the 6 years after the 36-month visit as an outcome. Results Among the 1746 analyzed, 19% met the inverse OARSI-OMERACT criteria. Meeting the inverse OARSI-OMERACT criteria was associated with almost double the odds of experiencing concurrent worsening in radiographic KOA severity (OR 1.89, 95% CI 1.32–2.70) or decline in walking speed (OR 1.82, 95% CI 1.37–2.40). A knee meeting the inverse OARSI-OMERACT criteria was more likely to receive a knee replacement after the 36-month visit (23%) compared with a nonresponder (10%; HR 2.54, 95% CI 1.89–3.41). Conclusion The inverse OARSI-OMERACT criteria for worsening among people with KOA had good construct validity in relation to clinically relevant outcomes.

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A Randomized, Double-Blind, Placebo-Controlled Study of Venlafaxine XR in Out-Patients With Tension-Type Headache

Cephalalgia ◽

10.1111/j.1468-2982.2007.01300.x ◽

2007 ◽

Vol 27 (4) ◽

pp. 315-324 ◽

Cited By ~ 59

Author(s):

NP Zissis ◽

S Harmoussi ◽

N Vlaikidis ◽

D Mitsikostas ◽

T Thomaidis ◽

...

Keyword(s):

Extended Release ◽

International Headache Society ◽

Preliminary Evidence ◽

Tension Type Headache ◽

Controlled Study ◽

Number Needed To Treat ◽

Double Blind ◽

Headache Clinic ◽

Type Headache ◽

Number Needed To Harm

The aim of this study was to evaluate in a double-blind, randomized, placebo-controlled study the safety and efficacy of venlafaxine extended release (XR) in the prophylactic treatment of out-patients with tension-type headache (TTH) and no current depression or anxiety disorders. Sixty neurology and headache clinic out-patients meeting the International Headache Society diagnostic criteria for TTH were treated with venlafaxine XR (150 mg/day, n = 34) or placebo ( n = 26) for 12 weeks. The primary efficacy variable was the decline in number of days with headache. At end-point, the venlafaxine XR group had a significantly greater decrease in the number of days with headache compared with placebo ( P = 0.05). Differences with regard to secondary efficacy variables where not significant. The number needed to treat for responders (≥50% reduction in days with headache) was 3.48. Six patients in the venlafaxine XR group interrupted therapy due to adverse events, while no patients in the placebo group did so for the same reason. The number needed to harm was 5.58. This study provides preliminary evidence for the efficacy and safety of venlafaxine XR 150 mg/day in reducing the number of days with TTH.

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Effect of laser moxibustion for knee osteoarthritis: a multi-site double-blind randomized controlled trial

The Journal of Rheumatology ◽

10.3899/jrheum.200217 ◽

2020 ◽

pp. jrheum.200217

Author(s):

Ling Zhao ◽

Ke Cheng ◽

Fan Wu ◽

Jiong Du ◽

Yue Chen ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Pain Score ◽

Laser Treatment ◽

Pain Reduction ◽

Active Group ◽

Womac Pain ◽

Double Blind ◽

Womac Pain Score ◽

Clinically Significant ◽

And Function

Objective To examine the effects of laser moxibustion on pain and function in patients with knee osteoarthritis. Methods A double-blind randomized clinical trial (4-week treatment, 20-week follow-up) was conducted. A total of 392 symptomatic knee osteoarthritis patients with moderate or greater clinically significant knee pain were randomly assigned to laser treatment or sham laser control group (1:1). Twelve sessions of laser moxibustion treatments or sham on the acupuncture points at the affected knee(s) were performed three times a week for 4 weeks. The primary outcome measurement was change in WOMAC pain score from baseline to week 4. Results Among the 392 randomized participants, 364 (92.86%) completed the trial. The median WOMAC pain score significantly decreased at week 4 in the active group than in the sham group (2.1; 95% CI, 1.6 to 2.6; P < .01). At week 24, compared to the sham laser, active laser treatment resulted in significant pain reduction and function improvement (3.0; 95% CI, 2.5 to 3.6; P < 0.01, and 14.8; 95% CI, 11.9 to 17.6; P < .01, respectively). The physical component of the quality of life significantly improved in the active group than in the sham control at week 4 (3.2; 95% CI, 1.3 to 5.0; P = 0.001) up to week 24 (5.1; 95% CI, 3.3 to 7.0; P < .001). No serious adverse effects were reported. Conclusion Laser moxibustion resulted in statistically and clinically significant pain reduction and function improvement following a 4-week treatment in patients with knee osteoarthritis. Keywords: 10.6μm laser moxibustion, knee osteoarthritis, pain, traditional Chinese medicine, phototherapy

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Pimavanserin for the treatment of Parkinson’s disease psychosis: number needed to treat, number needed to harm, and likelihood to be helped or harmed

CNS Spectrums ◽

10.1017/s1092852917000736 ◽

2017 ◽

Vol 23 (3) ◽

pp. 228-238 ◽

Cited By ~ 7

Author(s):

Leslie Citrome ◽

James C. Norton ◽

Kathy Chi-Burris ◽

George Demos

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Adverse Event ◽

Clinical Response ◽

Number Needed To Treat ◽

Double Blind ◽

Response Versus ◽

Tolerability Data ◽

Number Needed To Harm ◽

Receptor Inverse Agonist

ObjectiveOur aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH).MethodsCategorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event.ResultsNNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are <10, and as robust as 4. NNH values for tolerability outcomes for pimavanserin 34 mg/d (as well as for doses that range from 8.5 to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson’s disease) versus discontinuation due to an adverse event.ConclusionsUsing the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

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Effect of laser moxibustion for knee osteoarthritis: a multi-site double-blind randomized controlled trial

10.21203/rs.2.20523/v1 ◽

2020 ◽

Author(s):

Ling Zhao ◽

Ke Cheng ◽

Fan Wu ◽

Jiong Du ◽

Yue Chen ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Laser Treatment ◽

Pain Reduction ◽

Active Group ◽

Osteoarthritis Of The Knee ◽

Womac Pain ◽

Sham Control ◽

Double Blind ◽

Significant Pain ◽

And Function

Abstract Background A laser device that mimics traditional moxibustion without smoke may be effective and safe for treating patients with knee osteoarthritis.Methods A double-blind randomized clinical trial was conducted. A total of 392 patients with osteoarthritis of the knee were randomly assigned to receive laser treatment or sham control three times a week for 4 weeks with 20-week follow-up. Primary outcomes were changes in the WOMAC pain scores at week 4. Results Among the 392 randomized participants, 364 (92.86%) completed the trial. The median WOMAC pain score significantly decreased at week 4 in the active group than in the sham group (2.2; 95% CI, 1.7 to 2.8; P < .01). At week 24, compared to the sham laser, active laser treatment resulted in significant pain reduction and function improvement (3.3; 95% CI, 2.7 to 3.9; P < 0.01, and 15.7; 95% CI, 12.8 to 18.8; P < .01, respectively). The physical component of the quality of life significantly improved in the active group than in the sham control at week 4 (3.0; 95% CI, 1.1 to 4.9; P = 0.002) up to week 24 (5.1; 95% CI, 3.2 to 7.0; P < .001). No serious adverse effects were reported. Conclusion Laser moxibustion resulted in statistically and clinically significant pain reduction and function improvement following a 4-week treatment in patients with knee osteoarthritis.

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The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400692 ◽

2019 ◽

Vol 10 (1) ◽

pp. 199-210 ◽

Cited By ~ 1

Author(s):

Chuanman Zhou ◽

Jintao Luo ◽

Xiaohui He ◽

Qian Zhou ◽

Yunxia He ◽

...

Keyword(s):

Plant Hormone ◽

Neuronal Excitability ◽

Resting Membrane Potential ◽

Loss Of Function ◽

Wild Type ◽

C Elegans ◽

Link Type ◽

Complex Functions ◽

And Function ◽

Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

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