scholarly journals The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis

2015 ◽  
Vol 19 (12) ◽  
pp. 1-188 ◽  
Author(s):  
Susan Ball ◽  
Jane Vickery ◽  
Jeremy Hobart ◽  
Dave Wright ◽  
Colin Green ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Economic Evaluation ◽  
Treatment Effect ◽  
Treatment Effects ◽  
Rating Scales ◽  
Measurement Instruments ◽  
Double Blind ◽  
Significant Treatment ◽  
Parallel Group ◽  
Disease Modifying

BackgroundThe Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ9-tetrahydrocannabinol (Δ9-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS.ObjectivesThere were three objectives in the CUPID study: (1) to evaluate whether or not Δ9-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ9-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS.DesignThe CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ9-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken.SettingTwenty-seven UK sites.ParticipantsAdults aged 18–65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0–6.5.InterventionsOral Δ9-THC (maximum 28 mg/day) or matching placebo.Assessment visitsThree and 6 months, and then 6-monthly up to 36 or 42 months.Main outcome measuresPrimary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs).ResultsEffectiveness– recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. Primary outcomes: no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active–placebo) –0.9 points (95% CI –2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects.Safety– at least one serious adverse event: 35% and 28% of active and placebo patients, respectively.RMT analyses– scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect.Economic evaluation– estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs.ConclusionsThe CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection.Trial registrationCurrent Controlled Trials ISRCTN62942668.FundingThe National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full inHealth Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

scholarly journals Estimating treatment effect for individuals with progressive multiple sclerosis using deep learning

2021 ◽  
Author(s):  
Jean-Pierre R Falet ◽  
Joshua Durso-Finley ◽  
Brennan Nichyporuk ◽  
Julien Schroeter ◽  
Francesca Bovis ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Treatment Effect ◽  
Progressive Multiple Sclerosis ◽  
Average Treatment Effect ◽  
Significant Treatment ◽  
Average Treatment ◽  
Cd20 Antibody ◽  
Disease Modifying ◽  
Anti Cd20

Modeling treatment effect could identify a subgroup of individuals who experience greater benefit from disease modifying therapy, allowing for predictive enrichment to increase the power of future clinical trials. We use deep learning to estimate the conditional average treatment effect for individuals taking disease modifying therapies for multiple sclerosis, using their baseline clinical and imaging characteristics. Data were obtained as part of three placebo-controlled randomized clinical trials: ORATORIO, OLYMPUS and ARPEGGIO, investigating the efficacy of ocrelizumab, rituximab and laquinimod, respectively. A shuffled mix of participants having received ocrelizumab or rituximab, anti-CD20-antibodies, was separated into a training (70%) and testing (30%) dataset, but we also performed nested cross-validation to improve the generalization error estimate. Data from ARPEGGIO served as additional external validation. An ensemble of multitask multilayer perceptrons was trained to predict the rate of disability progression on both active treatment and placebo to estimate the conditional average treatment effect. The model was able to separate responders and non-responders across a range of predicted effect sizes. Notably, the average treatment effect for the anti-CD20-antibody test set during nested cross-validation was significantly greater when selecting the model's prediction for the top 50% (HR 0.625, p=0.008) or the top 25% (HR 0.521, p=0.013) most responsive individuals, compared to HR 0.835 (p=0.154) for the entire group. The model trained on the anti-CD20-antibody dataset could also identify responders to laquinimod, finding a significant treatment effect in the top 30% of individuals (HR 0.352, p=0.043). We observed enrichment across a broad range of baseline features in the responder subgroups: younger, more men, shorter disease duration, higher disability scores, and more lesional activity. By simulating a 1-year study where only the 50% predicted to be most responsive are randomized, we could achieve 80% power to detect a significant difference with 6 times less participants than a clinical trial without enrichment. Subgroups of individuals with primary progressive multiple sclerosis who respond favourably to disease modifying therapies can therefore be identified based on their baseline characteristics, even when no significant treatment effect can be found at the whole-group level. The approach allows for predictive enrichment of future clinical trials, as well as personalized treatment selection in the clinic.

scholarly journals Improvement in relapse recovery with peginterferon beta-1a in patients with multiple sclerosis

2016 ◽  
Vol 2 ◽  
pp. 205521731667664 ◽  
Author(s):  
Thomas F Scott ◽  
Bernd C Kieseier ◽  
Scott D Newsome ◽  
Douglas L Arnold ◽  
Xiaojun You ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Treatment Effect ◽  
Disability Progression ◽  
Double Blind ◽  
Advance Study ◽  
Treatment Groups ◽  
Parallel Group ◽  
Relapsing Remitting ◽  
Post Hoc ◽  
Relapsing Remitting Multiple Sclerosis

Background Subcutaneous peginterferon beta-1a every 2 weeks significantly affects clinical outcomes in patients with relapsing–remitting multiple sclerosis (RRMS). Objectives To explore relationships between relapses and worsening of disability in patients with RRMS, and assess the treatment effect of peginterferon beta-1a on relapse recovery. Methods Post-hoc analysis of the 2-year, randomized, double-blind, parallel-group, Phase 3 ADVANCE study. The severity of relapses, proportion of patients with relapses associated with residual disability (onset of 24-week confirmed disability progression (CDP) within 90 days following a relapse), and persistence of changes in Functional Systems Scores, were compared between treatment groups. Results Subcutaneous peginterferon beta-1a every 2 weeks significantly reduced the proportion of patients experiencing relapse associated with CDP over 2 years (6.6%, compared with 15.1% of patients who received placebo in Year 1; p = 0.02). Reduction in relapses associated with residual disability was greater than the treatment effect on overall relapse rate, and occurred despite similar relapse severity across treatment groups. Conclusions The beneficial effect of peginterferon beta-1a on risk of CDP may be attributable to the combination of an overall reduction in the risk of relapses and improvement in recovery from relapses, thus limiting further disability progression. Trial registration ClinicalTrials.gov identifier: NCT00906399

scholarly journals Effects of Vitamin D Supplementation on Surrogate Markers of Fertility in PCOS Women: A Randomized Controlled Trial

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 547
Author(s):  
Elisabeth Lerchbaum ◽  
Verena Theiler-Schwetz ◽  
Martina Kollmann ◽  
Monika Wölfler ◽  
Stefan Pilz ◽  
...  
Keyword(s):  
Vitamin D ◽  
Treatment Effect ◽  
Polycystic Ovary ◽  
Controlled Trial ◽  
Dehydroepiandrosterone Sulfate ◽  
Vitamin D Supplementation ◽  
Double Blind ◽  
Significant Treatment ◽  
Hydroxyvitamin D ◽  
Randomized Controlled

Vitamin D (VD) might play an important role in polycystic ovary syndrome (PCOS) and female fertility. However, evidence from randomized controlled trials (RCT) is sparse. We examined VD effects on anti-Müllerian hormone (AMH) and other endocrine markers in PCOS and non-PCOS women. This is a post hoc analysis of a single-center, double-blind RCT conducted between December 2011 and October 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. We included 180 PCOS women and 150 non-PCOS women with serum 25-hydroxyvitamin D (25(OH)D) concentrations <75 nmol/L in the trial. We randomized subjects to receive 20,000 IU of VD3/week (119 PCOS, 99 non-PCOS women) or placebo (61 PCOS, 51 non-PCOS women) for 24 weeks. Outcome measures were AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, dehydroepiandrosterone sulfate, and androstenedione. In PCOS women, we observed a significant treatment effect on FSH (mean treatment effect 0.94, 95% confidence interval [CI] 0.087 to 1.799, p = 0.031) and LH/FSH ratio (mean treatment effect −0.335, 95% CI −0.621 to 0.050, p = 0.022), whereas no significant effect was observed in non-PCOS women. In PCOS women, VD treatment for 24 weeks had a significant effect on FSH and LH/FSH ratio but no effect on AMH levels.

scholarly journals A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis

Neurology ◽  
2020 ◽  
Vol 95 (8) ◽  
pp. e1027-e1040 ◽  
Author(s):  
Gavin Giovannoni ◽  
Volker Knappertz ◽  
Joshua R. Steinerman ◽  
Aaron P. Tansy ◽  
Thomas Li ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Primary Endpoint ◽  
Treatment Effect ◽  
Brain Volume ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Phase 2 ◽  
Significant Treatment Effect ◽  
Significant Treatment ◽  
Primary Progressive

ObjectiveTo evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS).MethodsIn the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events.ResultsA total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26–0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%).ConclusionsLaquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.Clinicaltrials.gov identifierNCT02284568.Classification of evidenceThis study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS.

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis

2012 ◽  
Vol 18 (9) ◽  
pp. 1269-1277 ◽  
Author(s):  
T Saida ◽  
S Kikuchi ◽  
Y Itoyama ◽  
Q Hao ◽  
T Kurosawa ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Controlled Trial ◽  
Japanese Patients ◽  
Double Blind ◽  
Parallel Group ◽  
Safety Outcomes ◽  
Secondary Endpoints ◽  
Caucasian Patients

Background: Fingolimod (FTY720) has previously shown clinical efficacy in phase II/III studies of predominantly Caucasian populations with multiple sclerosis (MS). Objectives: To report six-month efficacy and safety outcomes in Japanese patients with relapsing MS treated with fingolimod. Methods: In this double-blind, parallel-group, phase II study, 171 Japanese patients with relapsing MS were randomized to receive once-daily fingolimod 0.5 mg or 1.25 mg, or matching placebo for six months. The primary and secondary endpoints were the percentages of patients free from gadolinium (Gd)-enhanced lesions at months 3 and 6, and relapses over six months, respectively; safety outcomes were also assessed. Results: 147 patients completed the study. Higher proportions of patients were free from Gd-enhanced lesions at months 3 and 6 with fingolimod (0.5 mg: 70%, p = 0.004; 1.25 mg: 86%, p < 0.001) than with placebo (40%). Odds ratios for the proportions of relapse-free patients over six months favoured fingolimod versus placebo but were not significant. Adverse events related to fingolimod included transient bradycardia and atrioventricular block at treatment initiation, and elevated liver enzyme levels. Conclusions: This study demonstrated the clinical efficacy of fingolimod for the first time in Japanese patients with MS, consistent with the established effects of fingolimod in Caucasian patients.

scholarly journals Oral nitrate supplementation to enhance pulmonary rehabilitation in COPD: ON-EPIC a multicentre, double-blind, placebo-controlled, randomised parallel group study

Thorax ◽  
2020 ◽  
Vol 75 (7) ◽  
pp. 547-555
Author(s):  
Matthew J Pavitt ◽  
Rebecca Jayne Tanner ◽  
Adam Lewis ◽  
Sara Buttery ◽  
Bhavin Mehta ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Active Treatment ◽  
Treatment Effect ◽  
Pulmonary Rehabilitation ◽  
Activity Level ◽  
Double Blind ◽  
Dietary Nitrate ◽  
Double Blind Placebo ◽  
Parallel Group ◽  
Nitrate Supplementation

RationaleDietary nitrate supplementation has been proposed as a strategy to improve exercise performance, both in healthy individuals and in people with COPD. We aimed to assess whether it could enhance the effect of pulmonary rehabilitation (PR) in COPD.MethodsThis double-blind, placebo-controlled, parallel group, randomised controlled study performed at four UK centres, enrolled adults with Global Initiative for Chronic Obstructive Lung Disease grade II–IV COPD and Medical Research Council dyspnoea score 3–5 or functional limitation to undertake a twice weekly 8-week PR programme. They were randomly assigned (1:1) to either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate), or placebo nitrate-deplete BRJ, consumed 3 hours prior to undertaking each PR session. Allocation used computer-generated block randomisation.MeasurementsThe primary outcome was change in incremental shuttle walk test (ISWT) distance. Secondary outcomes included quality of life, physical activity level, endothelial function via flow-mediated dilatation, fat-free mass index and blood pressure parameters.Results165 participants were recruited, 78 randomised to nitrate-rich BRJ and 87 randomised to placebo. Exercise capacity increased more with active treatment (n=57) than placebo (n=65); median (IQR) change in ISWT distance +60 m (10, 85) vs +30 m (0, 70), estimated treatment effect 30 m (95% CI 10 to 40); p=0.027. Active treatment also impacted on systolic blood pressure: treatment group −5.0 mm Hg (−5.0, –3.0) versus control +6.0 mm Hg (−1.0, 15.5), estimated treatment effect −7 mm Hg (95% CI 7 to −20) (p<0.0005). No significant serious adverse events or side effects were reported.ConclusionsDietary nitrate supplementation appears to be a well-tolerated and effective strategy to augment the benefits of PR in COPD.Trial registration numberISRCTN27860457.

Proof of concept studies for tissue-protective agents in multiple sclerosis

2009 ◽  
Vol 15 (5) ◽  
pp. 542-546 ◽  
Author(s):  
LR Mehta ◽  
SR Schwid ◽  
DL Arnold ◽  
GR Cutter ◽  
S Aradhye ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Final Visit ◽  
Proof Of Concept ◽  
Eligibility Criteria ◽  
Double Blind ◽  
Protective Agents ◽  
Parallel Group ◽  
Acute Exacerbations ◽  
Study Designs ◽  
Size Estimates

Background There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). Methods and Objectives We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. Results Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3–6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. Conclusions The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

Bimonthly assessment of magnetization transfer magnetic resonance imaging parameters in multiple sclerosis: a 14-month, multicentre, follow-up study

2010 ◽  
Vol 16 (3) ◽  
pp. 325-331 ◽  
Author(s):  
S. Mesaros ◽  
MA Rocca ◽  
MP Sormani ◽  
P. Valsasina ◽  
C. Markowitz ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Treatment Effect ◽  
Repeated Measures ◽  
Magnetization Transfer ◽  
Random Effect ◽  
Lesion Volume ◽  
Sample Sizes ◽  
Double Blind ◽  
Over Time

This study was performed to assess the temporal evolution of damage within lesions and the normal-appearing white matter, measured using frequent magnetization transfer (MT) MRI, in relapsing—remitting multiple sclerosis (RRMS). The relationship of MT ratio (MTR) changes with measures of lesion burden, and the sample sizes needed to demonstrate a treatment effect on MTR metrics in placebo-controlled MS trials were also investigated. Bimonthly brain conventional and MT MRI scans were acquired from 42 patients with RRMS enrolled in the placebo arm of a 14-month, double-blind trial. Longitudinal MRI changes were evaluated using a random effect linear model accounting for repeated measures, and adjusted for centre effects. The Expanded Disability Status Scale (EDSS) score remained stable over the study period. A weak, but not statistically significant, decrease over time was detected for normal-appearing brain tissue (NABT) average MTR (—0.02% per visit; p = 0.14), and MTR peak height (—0.15 per visit; p = 0.17), while average lesion MTR showed a significant decrease over the study period (—0.07% per visit; p = 0.03). At each visit, all MTR variables were significantly correlated with T2 lesion volume (LV) (average coefficients of correlation ranging from —0.54 to —0.28, and p-values from <0.001 to 0.02). At each visit, NABT average MTR was also significantly correlated with T1-hypointense LV (average coefficient of correlation = —0.57, p < 0.001). The estimation of the sample sizes required to demonstrate a reduction of average lesion MTR (the only parameter with a significant decrease over the follow-up) ranged from 101 to 154 patients to detect a treatment effect of 50% in a 1-year trial with a power of 90%. The steady correlation observed between conventional and MT MRI measures over time supports the hypothesis of axonal degeneration of fibres passing through focal lesions as one of the factors contributing to the overall MS burden.

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