Certolizumab pegol plus methotrexate 5-year results from the rheumatoid arthritis prevention of structural damage (RAPID) 2 randomized controlled trial and long-term extension in rheumatoid arthritis patients

IntroductionAs patients with rheumatoid arthritis (RA) receive treatment with anti-tumour necrosis factors over several years, it is important to evaluate their long-term safety and efficacy. The objective of this study was to examine the safety and benefits of certolizumab pegol (CZP)+methotrexate (MTX) treatment for almost 5 years in patients with RA.MethodsPatients who completed the 24-week Rheumatoid Arthritis Prevention of Structural Damage (RAPID) 2 randomized controlled trial (RCT; {"type":"clinical-trial","attrs":{"text":"NCT00160602","term_id":"NCT00160602"}}NCT00160602), or who were American College of Rheumatology (ACR) 20 non-responders at Week 16, entered the open-label extension (OLE; {"type":"clinical-trial","attrs":{"text":"NCT00160641","term_id":"NCT00160641"}}NCT00160641). After ≥6 months treatment with CZP 400 mg every two weeks (Q2W), dose was reduced to 200 mg Q2W, the approved maintenance dose. Safety data are presented from all patients who received ≥1 dose CZP (Safety population, n=612). Efficacy data are presented to Week 232 for the intent-to-treat (ITT, n=492) and Week 24 CZP RCT Completer (n=342) populations, and through 192 weeks of dose-reduction for the Dose-reduction population (patients whose CZP dose was reduced to 200 mg, n=369). Radiographic progression (modified total Sharp score change from RCT baseline >0.5) to Week 128 is reported for the Week 24 CZP Completers.ResultsIn the RCT, 619 patients were randomized to CZP+MTX (n=492) or placebo+MTX (n=127). Overall, 567 patients (91.6%) entered the OLE: 447 CZP and 120 placebo patients. Of all randomized patients, 358 (57.8%) were ongoing at Week 232. Annual drop-out rates during the first four years ranged from 8.4–15.0%. Event rates per 100 patient-years were 163.0 for adverse events (AEs) and 15.7 for serious AEs. Nineteen patients (3.1%) had fatal AEs (incidence rate=0.8). Clinical improvements in the RCT were maintained to Week 232 in the CZP Completers: mean Disease Activity Score 28 (Erythrocyte Sedimentation Rate) change from baseline was −3.4 and ACR20/50/70 responses 68.4%/47.1%/25.1% (non-responder imputation). Similar improvements observed in the ITT were maintained following dose-reduction. 73.2% of CZP Completers had no radiographic progression at Week 128.ConclusionsIn patients with active RA despite MTX therapy, CZP was well tolerated, with no new safety signals identified. CZP provided sustained improvements in clinical outcomes for almost 5 years.

Trial registration

ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00160602","term_id":"NCT00160602"}}NCT00160602 and {"type":"clinical-trial","attrs":{"text":"NCT00160641","term_id":"NCT00160641"}}NCT00160641. Registered 8 September 2005.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0767-2) contains supplementary material, which is available to authorized users.     

Pitavastatin and Atorvastatin Double-Blind Randomized ComPArative Study among HiGh-Risk Patients,Including ThOse with Type 2 Diabetes Mellitus,in Taiwan (PAPAGO-T Study)

Background

Evidence about the efficacy and safety of statin treatment in high-risk patients with hypercholesterolemia is available for some populations, but not for ethnic Chinese. To test the hypothesis that treatment with pitavastatin (2 mg/day) is not inferior to treatment with atorvastatin (10 mg/day) for reducing low-density lipoprotein cholesterol (LDL-C), a 12-week multicenter collaborative randomized parallel-group comparative study of high-risk ethnic Chinese patients with hypercholesterolemia was conducted in Taiwan. In addition, the effects on other lipid parameters, inflammatory markers, insulin-resistance-associated biomarkers and safety were evaluated.

Methods and Results

Between July 2011 and April 2012, 251 patients were screened, 225 (mean age: 58.7 ± 8.6; women 38.2% [86/225]) were randomized and treated with pitavastatin (n = 112) or atorvastatin (n = 113) for 12 weeks. Baseline characteristics in both groups were similar, but after 12 weeks of treatment, LDL-C levels were significantly lower: pitavastatin group = −35.0 ± 14.1% and atorvastatin group = −38.4 ± 12.8% (both: p < 0.001). For the subgroup with diabetes mellitus (DM) (n = 125), LDL-C levels (−37.1 ± 12.9% vs. −38.0 ± 13.1%, p = 0.62) were similarly lowered after either pitavastatin (n = 63) or atorvastatin (n = 62) treatment. Triglycerides, non-high density lipoprotein cholesterol, and apoprotein B were similarly and significantly lower in both treatment groups. In non-lipid profiles, HOMA-IR and insulin levels were higher to a similar degree in both statin groups. Hemoglobin A₁C was significantly (p = 0.001) higher in the atorvastatin group but not in the pitavastatin group. Both statins were well tolerated, and both groups had a similar low incidence of treatment-emergent adverse events.

Conclusion

Both pitavastatin (2 mg/day) and atorvastatin (10 mg/day) were well tolerated, lowered LDL-C, and improved the lipid profile to a comparable degree in high-risk Taiwanese patients with hypercholesterolemia.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01386853","term_id":"NCT01386853"}}NCT01386853 http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01386853","term_id":"NCT01386853"}}NCT01386853?term={"type":"clinical-trial","attrs":{"text":"NCT01386853","term_id":"NCT01386853"}}NCT01386853&rank=1     

Repetitive Transcranial Magnetic Stimulation in Cervical Dystonia: Effect of Site and Repetition in a Randomized Pilot Trial

Dystonia is characterized by abnormal posturing due to sustained muscle contraction, which leads to pain and significant disability. New therapeutic targets are needed in this disorder. The objective of this randomized, sham-controlled, blinded exploratory study is to identify a specific motor system target for non-invasive neuromodulation and to evaluate this target in terms of safety and tolerability in the cervical dystonia (CD) population. Eight CD subjects were given 15-minute sessions of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (MC), dorsal premotor cortex (dPM), supplementary motor area (SMA), anterior cingulate cortex (ACC) and a sham condition with each session separated by at least two days. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score was rated in a blinded fashion immediately pre- and post-intervention. Secondary outcomes included physiology and tolerability ratings. The mean change in TWSTRS severity score by site was 0.25 ± 1.7 (ACC), -2.9 ± 3.4 (dPM), -3.0 ± 4.8 (MC), -0.5 ± 1.1 (SHAM), and -1.5 ± 3.2 (SMA) with negative numbers indicating improvement in symptom control. TWSTRS scores decreased from Session 1 (15.1 ± 5.1) to Session 5 (11.0 ± 7.6). The treatment was tolerable and safe. Physiology data were acquired on 6 of 8 subjects and showed no change over time. These results suggest rTMS can modulate CD symptoms. Both dPM and MC are areas to be targeted in further rTMS studies. The improvement in TWSTRS scores over time with multiple rTMS sessions deserves further evaluation.

Trial Registration

ClinicalTrials.gov NCT01859247     

DNA Vaccine Delivered by a Needle-Free Injection Device Improves Potency of Priming for Antibody and CD8+ T-Cell Responses after rAd5 Boost in a Randomized Clinical Trial

Background

DNA vaccine immunogenicity has been limited by inefficient delivery. Needle-free delivery of DNA using a CO₂-powered Biojector® device was compared to delivery by needle and syringe and evaluated for safety and immunogenicity.

Methods

Forty adults, 18–50 years, were randomly assigned to intramuscular (IM) vaccinations with DNA vaccine, VRC-HIVDNA016-00-VP, (weeks 0, 4, 8) by Biojector® 2000™ or needle and syringe (N/S) and boosted IM at week 24 with VRC-HIVADV014-00-VP (rAd5) with N/S at 10¹⁰ or 10¹¹ particle units (PU). Equal numbers per assigned schedule had low (≤500) or high (>500) reciprocal titers of preexisting Ad5 neutralizing antibody.

Results

120 DNA and 39 rAd5 injections were given; 36 subjects completed follow-up research sample collections. IFN-γ ELISpot response rates were 17/19 (89%) for Biojector® and 13/17 (76%) for N/S delivery at Week 28 (4 weeks post rAd5 boost). The magnitude of ELISpot response was about 3-fold higher in Biojector® compared to N/S groups. Similar effects on response rates and magnitude were observed for CD8+, but not CD4+ T-cell responses by ICS. Env-specific antibody responses were about 10-fold higher in Biojector-primed subjects.

Conclusions

DNA vaccination by Biojector® was well-tolerated and compared to needle injection, primed for greater IFN-γ ELISpot, CD8+ T-cell, and antibody responses after rAd5 boosting.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00109629","term_id":"NCT00109629"}}NCT00109629     

How reliable is internet-based self-reported identity,socio-demographic and obesity measures in European adults?

In e-health intervention studies, there are concerns about the reliability of internet-based, self-reported (SR) data and about the potential for identity fraud. This study introduced and tested a novel procedure for assessing the validity of internet-based, SR identity and validated anthropometric and demographic data via measurements performed face-to-face in a validation study (VS). Participants (n = 140) from seven European countries, participating in the Food4Me intervention study which aimed to test the efficacy of personalised nutrition approaches delivered via the internet, were invited to take part in the VS. Participants visited a research centre in each country within 2 weeks of providing SR data via the internet. Participants received detailed instructions on how to perform each measurement. Individual’s identity was checked visually and by repeated collection and analysis of buccal cell DNA for 33 genetic variants. Validation of identity using genomic information showed perfect concordance between SR and VS. Similar results were found for demographic data (age and sex verification). We observed strong intra-class correlation coefficients between SR and VS for anthropometric data (height 0.990, weight 0.994 and BMI 0.983). However, internet-based SR weight was under-reported (Δ −0.70 kg [−3.6 to 2.1], p < 0.0001) and, therefore, BMI was lower for SR data (Δ −0.29 kg m⁻² [−1.5 to 1.0], p < 0.0001). BMI classification was correct in 93 % of cases. We demonstrate the utility of genotype information for detection of possible identity fraud in e-health studies and confirm the reliability of internet-based, SR anthropometric and demographic data collected in the Food4Me study.Trial registration: {"type":"clinical-trial","attrs":{"text":"NCT01530139","term_id":"NCT01530139"}}NCT01530139 (http://clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT01530139","term_id":"NCT01530139"}}NCT01530139).

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-015-0476-0) contains supplementary material, which is available to authorized users.     

Preventing Loss of Independence through Exercise (PLIé): A Pilot Clinical Trial in Older Adults with Dementia

BackgroundCurrent dementia medications have small effect sizes, many adverse effects and do not change the disease course. Therefore, it is critically important to study alternative treatment strategies. The goal of this study was to pilot-test a novel, integrative group exercise program for individuals with mild-to-moderate dementia called Preventing Loss of Independence through Exercise (PLIÉ), which focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection.MethodsWe performed a 36-week cross-over pilot clinical trial to compare PLIÉ with usual care (UC) at an adult day program for individuals with dementia in San Francisco, CA. Assessments of physical performance, cognitive function, physical function, dementia-related behaviors, quality of life and caregiver burden were performed by blinded assessors at baseline, 18 weeks (cross-over) and 36 weeks. Our primary outcomes were effect sizes based on between-group comparisons of change from baseline to 18 weeks; secondary outcomes were within-group comparisons of change before and after cross-over.ResultsTwelve individuals enrolled (7 PLIÉ, 5 UC) and 2 withdrew (1 PLIÉ, 18 weeks; 1 UC, 36 weeks). Participants were 82% women (mean age, 84 ± 4 years); caregivers were 82% daughters (mean age, 56 ± 13 years). Effect sizes were not statistically significant but suggested potentially clinically meaningful (≥0.25 SDs) improvement with PLIÉ versus UC for physical performance (Cohen’s D: 0.34 SDs), cognitive function (0.76 SDs) and quality of life (0.83 SDs) as well as for caregiver measures of participant’s quality of life (0.33 SDs) and caregiver burden (0.49 SDs). Results were similar when within-group comparisons were made before and after cross-over.ConclusionsPLIÉ is a novel, integrative exercise program that shows promise for improving physical function, cognitive function, quality of life and caregiver burden in individuals with mild-to-moderate dementia. Larger randomized, controlled trials are warranted.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01371214","term_id":"NCT01371214"}}NCT01371214     

Serological identification of fast progressors of structural damage with rheumatoid arthritis

Introduction

Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruction. We investigated whether baseline serum C1M levels could identify structural progressors and if the biomarker levels changed during anti-inflammatory treatment with tocilizumab (TCZ).

Methods

The LITHE-biomarker study ({"type":"clinical-trial","attrs":{"text":"NCT00106535","term_id":"NCT00106535"}}NCT00106535, n = 585) was a one-year phase III, double-blind, placebo (PBO)-controlled, parallel group study of TCZ 4 or 8 mg/kg every four weeks, in RA patients on stable doses of methotrexate (MTX). Spearman''s ranked correlation was used to assess the correlation between baseline C1M levels and structural progression at baseline and at weeks 24 and 52. Multivariate regression was performed for delta structural progression. Change in C1M levels were studied as a function of time and treatment.

Results

At baseline, C1M was significantly correlated to C-reactive protein (P <0.0001), visual analog scale pain (P <0.0001), disease activity score28-erythrocyte sedimentation rate (DAS28-ESR) (P <0.0001), joint space narrowing (JSN) (P = 0.0056) and modified total Sharp score (mTSS) (P = 0.0006). Baseline C1M was significantly correlated with delta-JSN at Week 24 (R² = 0.09, P = 0.0001) and at Week 52 (R² = 0.27, P <0.0001), and with delta-mTSS at 24 weeks (R² = 0.006, P = 0.0015) and strongly at 52 weeks (R² = 0.013, P <0.0001) in the PBO group. C1M levels were dose-dependently reduced in the TCZ + MTX group.

Conclusions

Baseline C1M levels correlated with worsening joint structure over one year. Serum C1M levels may enable identification of those RA patients that are in most need of aggressive treatment

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00106535","term_id":"NCT00106535"}}NCT00106535     

Simplification to Abacavir/Lamivudine + Atazanavir Maintains Viral Suppression and Improves Bone and Renal Biomarkers in ASSURE,a Randomized,Open Label,Non-Inferiority Trial

Objective

Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study’s primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients.

Design

This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥6 months with no history of virologic failure and whose HIV-1 RNA had been ≤75 copies/mL on 2 consecutive measurements including screening. Patients were randomized 1∶2 to continue current treatment or simplify to ABC/3TC+ATV.

Methods

The primary endpoint was the proportion of patients with HIV-RNA<50 copies/mL at Week 24 by the Time to Loss of Virologic Response (TLOVR) algorithm. Secondary endpoints included alternative measures of efficacy, adverse events (AEs), and fasting lipids. Exploratory endpoints included inflammatory, coagulation, bone, and renal biomarkers.

Results

After 24 weeks, ABC/3TC+ATV (n = 199) was non-inferior to TDF/FTC+ATV/r (n = 97) by both the primary analysis (87% in both groups) and all secondary efficacy analyses. Rates of grade 2–4 AEs were similar between the two groups (40% vs 37%, respectively), but an excess of hyperbilirubinemia made the rate of grade 3–4 laboratory abnormalities higher in the TDF/FTC+ATV/r group (30%) compared with the ABC/3TC+ATV group (13%). Lipid levels were stable except for HDL cholesterol, which increased significantly in the ABC/3TC+ATV group. Bone and renal biomarkers improved significantly between baseline and Week 24 in patients taking ABC/3TC+ATV, and the difference between groups was significant at Week 24. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups.

Conclusions

After 24 weeks, simplification to ABC/3TC+ATV from TDF/FTC+ATV/r maintained viral suppression was well-tolerated, and led to improvements in bone and renal biomarkers and HDL cholesterol.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01102972","term_id":"NCT01102972"}}NCT01102972 GlaxoSmithKline Clinical Study Register #113734     

Existing joint erosions increase the risk of joint space narrowing independently of clinical synovitis in patients with early rheumatoid arthritis

IntroductionClinical synovitis is often associated with damage to bone and cartilage. Previous data have suggested that joint erosions (JE) are more prevalent than joint space narrowing (JSN) and that the two processes are partly independent of each other. The objective of this study was to evaluate whether the presence of JE in an individual joint can lead to development of JSN and if existing JSN leads to new onset of JE, in the absence of synovitis.MethodsThe Prospective Multi-Centre Randomised, Double-Blind, Active Comparator-Controlled, Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNFα Antibody Adalimumab Given Every Second Week With Methotrexate Given Weekly and the Combination of Adalimumab and Methotrexate Administered Over 2 Years in Patients With Early Rheumatoid Arthritis (PREMIER) enrolled early rheumatoid arthritis (RA) patients who were randomized to one of three treatments: methotrexate (MTX), adalimumab (ADA), or ADA + MTX. All evaluable joints with JE and JSN measures at 26 and 52 weeks and synovitis assessments from week 26 to 52 were included. Synovitis was assessed every 2–8 weeks by swollen joint counts between weeks 26 and 52. Radiographs were taken at week 26 and 52. Two readers, blinded to time and sequence, scored 14 bilateral joints individually for JE and JSN. Multivariate logistic modeling was used to characterize the dependence of JE/JSN onset at 52 weeks. Analyses were performed based on treatment arm and were also performed within individual joints.ResultsJE and swelling were independently and comparably associated with onset of JSN at week 52. Assessment by individual joints indicated that existing JE, independent of swelling, was significantly associated with JSN onset in higher proportions of metatarsophalangeal (MTP; 7/10) than proximal interphalangeal (PIP; 1/8) or metacarpophalangeal (MCP; 1/10) joints. Treatment with ADA + MTX prevents JE/JSN progression independently of its ability to suppress synovitis and limits JE/JSN onset and progression in joints with existing damage.ConclusionsExisting JE predisposes individual joints to development of JSN independently of synovitis in the same joint. Weight-bearing MTP joints with JE may be at increased risk for JSN when compared with MCPs and PIPs.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00195663","term_id":"NCT00195663"}}NCT00195663. Registered 13 September 2005.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0626-1) contains supplementary material, which is available to authorized users.     

Habitual Functional Electrical Stimulation Therapy Improves Gait Kinematics and Walking Performance,but Not Patient-Reported Functional Outcomes,of People with Multiple Sclerosis who Present with Foot-Drop

Background

People with Multiple Sclerosis (pwMS) often experience a disturbed gait function such as foot-drop. The objective of this pilot study was to investigate the medium term effects of using Functional Electrical Stimulation (FES) to treat foot-drop over a period 12 weeks on gait and patient reported outcomes of pwMS.

Methods and Findings

Nine pwMS aged 35 to 64 (2 males, 7 females) were assessed on four occasions; four weeks before baseline, at baseline and after six weeks and twelve weeks of FES use. Joint kinematics and performance on the 10 meter and 2 minute walk tests (10WT, 2 minWT) were assessed with and without FES. Participants also completed the MS walking Scale (MSWS), MS impact scale (MSIS29), Fatigue Severity Score (FSS) and wore an activity monitor for seven days after each assessment. Compared to unassisted walking, FES resulted in statistically significant improvements in peak dorsiflexion in swing (p = 0.006), 10MWT (p = 0.006) and 2 minWT (p = 0.002). Effect sizes for the training effect, defined as the change from unassisted walking at baseline to that at 12 weeks, indicated improved ankle angle at initial contact (2.6°, 95% CI −1° to 4°, d = 0.78), and a decrease in perceived exertion over the 2 min walking tests (−1.2 points, 95% CI −5.7 to 3.4, d = −0.86). Five participants exceeded the Minimally Detectable Change (MDC) for a training effect on the 10mWT, but only two did so for the 2 minWT. No effects of the use of FES for 12 weeks were found for MSWS, MSIS29, FSS or step count.

Conclusion

Although FES to treat foot-drop appears to offer the potential for a medium term training effect on ankle kinematics and walking speed, this was not reflected in the patient reported outcomes. This observed lack of relationship between objective walking performance and patient reported outcomes warrants further investigation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01977287","term_id":"NCT01977287"}}NCT01977287     

Effect of Alpha Linolenic Acid Supplementation on Serum Prostate Specific Antigen (PSA): Results from the Alpha Omega Trial

Background

Alpha linolenic acid (ALA) is the major omega-3 fatty acid in the diet. Evidence on health effects of ALA is not conclusive, but some observational studies found an increased risk of prostate cancer with higher intake of ALA. We examined the effect of ALA supplementation on serum concentrations of prostate-specific antigen (PSA), a biomarker for prostate cancer.

Methods

The Alpha Omega Trial (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00127452","term_id":"NCT00127452"}}NCT00127452) was a double-blind, placebo-controlled trial of ALA and the fish fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) on the recurrence of cardiovascular disease, using a 2×2 factorial design. Blood was collected at the start and the end of the intervention period. The present analysis included 1622 patients with a history of a myocardial infarction, aged 60–80 years with an initial PSA concentration <4 ng/mL. They received either 2 g per day of ALA or placebo in margarine spreads for 40 months. T-tests and logistic regression were used to assess the effects of ALA supplementation on changes in serum PSA (both continuously and as a dichotomous outcome, cut-off point: >4 ng/mL).

Findings

Mean serum PSA increased by 0.42 ng/mL on placebo (n = 815) and by 0.52 ng/mL on ALA (n = 807), a difference of 0.10 (95% confidence interval: −0.02 to 0.22) ng/mL (P = 0·12). The odds ratio for PSA rising above 4 ng/mL on ALA versus placebo was 1.15 (95% CI: 0.84–1.58).

Interpretation

An additional amount of 2 g of ALA per day increased PSA by 0.10 ng/mL, but the confidence interval ranged from −0.02 to 0.22 ng/mL and included no effect. Therefore, more studies are needed to establish whether or not ALA intake has a clinically significant effect on PSA or prostate cancer.

Trial registration information

ClinicalTrials.gov; Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00127452","term_id":"NCT00127452"}}NCT00127452. URL: http://www.clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00127452","term_id":"NCT00127452"}}NCT00127452.     

The Salford Lung Study protocol: a pragmatic,randomised phase III real-world effectiveness trial in chronic obstructive pulmonary disease

Background

New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy.

Methods

Patients with chronic obstructive pulmonary disease (COPD), ≥40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data.

Conclusions

The Salford Lung Study is the world’s first pragmatic randomised controlled trial of a pre-licensed medication in COPD.

Trial registration

Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01551758","term_id":"NCT01551758"}}NCT01551758.     

A Randomized Comparative Trial of Continued Abacavir/Lamivudine plus Efavirenz or Replacement with Efavirenz/Emtricitabine/Tenofovir DF in Hypercholesterolemic HIV-1 Infected Individuals

BackgroundDrug choice and metabolic changes with antiretroviral therapy contribute to cardiovascular risk in persons with HIV-1 infection.MethodsA randomized, 12 week, open-label, comparative study of the impact on lipids of continuation of abacavir/lamivudine (ABC/3TC) plus efavirenz (EFV) or replacement with the single tablet regimen of EFV/emtricitabine/tenofovir DF (EFV/FTC/TDF) in hypercholesterolaemic subjects on successful antiretroviral therapy, with a 12-week extension with all subjects on EFV/FTC/TDF.Results157 subjects received study drug, 79 switched to EFV/FTC/TDF and 78 subjects continued ABC/3TC+EFV. At Week 12, 73 subjects on ABC/3TC+EFV switched to EFV/FTC/TDF. The switch was well tolerated and no subject experienced viral rebound. Median baseline fasting total cholesterol was 6.32mmol/L. 12 weeks following switch, the difference in the means (LSM) between treatment groups (EFV/FTC/TDF minus ABC/3TC+EFV) in total cholesterol change from baseline was -0.74mmol/l (95% CI −1.00, −0.47, p < 0.001). The median change from baseline in total cholesterol following switch in the EFV/FTC/TDF arm was -0.86mmol/l (p < 0.001) compared with +0.01mmol/l (p = 0.45) in the continuation arm at Week 12. Significant (p < 0.001) differences between treatment groups following switch were seen for all lipid fractions from baseline to Week 12: LDL cholesterol (−0.47 mmol/L [−0.70, −0.25]), HDL cholesterol (−0.15 mmol/L [−0.21, −0.08]), triglycerides (−0.43 mmol/L [-0.75, -0.11]), and non HDL cholesterol (−0.56 mmol/L [−0.80, −0.31]). In the extension phase, similar declines in total cholesterol were observed with a median change from Week 12 to Week 24 of −0.73mmol/L (p < 0.001).ConclusionsSwitching from ABC/3TC+EFV to EFV/FTC/TDF in persons with hypercholesterolemia maintains virological control and significantly improves key lipid parameters.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00615810","term_id":"NCT00615810"}}NCT00615810     

A Comparative Study on the Efficacy of Solifenacin Succinate in Patients with Urinary Frequency with or without Urgency

Objectives

Patients with overactive bladder (OAB) often have trouble perceiving urgency because of difficulties in distinguishing between urgency and desire to void. Empirical antimuscarinic treatment of patients with frequency only may be reasonable if conservative management has failed. We compared the efficacy of solifenacin in patients with frequency with or without urgency.

Materials and Methods

This multicenter, 12-week, open-label, comparative, non-inferiority clinical trial assessed whether the solifenacin efficacy for frequency without urgency is non-inferior to its efficacy for frequency with urgency. All patients had micturition frequency ≥8 voids/day with or without urgency. Primary efficacy variable: daily frequency change at 12 weeks relative to baseline. Secondary efficacy variables: change at 12 weeks relative to baseline in Patients'' Perception of Bladder Condition (PPBC), OAB Symptom Score (OABSS), and Benefit, Satisfaction, Willingness to continue (BSW) questionnaire.

Results

Of the 286 enrolled patients, 240 (83.9%) completed the study (without urgency n = 115; with urgency n = 125). Full dataset analysis revealed that the groups without and with urgency exhibited significant reductions in daily micturition frequency of −2.49±0.35 (mean ± standard error) and −2.63±0.37, respectively. The lower limit of the 95% two-sided CI of the comparison of the two group means was −1.14, which is smaller than the −0.8 margin of clinical equivalence. The two groups did not differ in improvement in PPBC, OABSS, or BSW scores. Both tolerated the treatment well.

Conclusions

It was not possible to verify that the solifenacin efficacy for frequency alone was non-inferior to its efficacy for OAB. Nevertheless, solifenacin tended to be effective for frequency regardless of urgency.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00979472","term_id":"NCT00979472"}}NCT00979472     

Golimumab in patients with active rheumatoid arthritis after treatment with tumor necrosis factor α inhibitors: findings with up to five years of treatment in the multicenter,randomized, double-blind,placebo-controlled,phase 3 GO-AFTER study

IntroductionThe aim of this study was to assess long-term golimumab therapy in rheumatoid arthritis (RA) patients who discontinued previous tumor necrosis factor-α (TNF)-inhibitor(s).MethodsPatients enrolled into this multicenter, randomized, double-blind, placebo-controlled study of active RA (≥4 tender, ≥4 swollen joints) received placebo (Group 1) or golimumab 50 mg (Group 2) or 100 mg (Group 3) injections every 4 weeks. Patients in Groups 1 and 2 with inadequate response at week 16 escaped to golimumab 50 and 100 mg, respectively. At week 24, Group 1 patients crossed-over to golimumab 50 mg, Group 2 continued golimumab 50/100 mg per escape status, and Group 3 maintained dosing. During the long-term-extension (LTE), golimumab 50 mg could be increased to 100 mg, and 100 mg could be decreased to 50 mg. Data through 5 years are reported for all patients (safety) and patients using methotrexate (efficacy, intention-to-treat (ITT) analysis with last-observation-carried-forward for missing data and non-responder imputation for unsatisfactory efficacy discontinuations).ResultsIn total, 459 of 461 randomized patients received the study agent, 304 of whom were methotrexate-treated and included in efficacy analyses. Through week 256, the proportions of methotrexate-treated patients achieving American-College-of-Rheumatology (ACR) responses were 37.6% to 47.0% for ACR20, 21.4% to 35.0% for ACR50, and 7.8% to 17.0% for ACR70 response across randomized groups. Golimumab safety through week 268 was generally consistent with that at week 24 and week 160 and other anti-TNF agents.ConclusionsIn some patients with active RA discontinuing previous TNF-antagonist therapy, golimumab safety and efficacy, assessed conservatively with ITT analyses, was confirmed through 5 years.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00299546","term_id":"NCT00299546"}}NCT00299546. Registered 03 March 2006.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0516-6) contains supplementary material, which is available to authorized users.     

A Double-Blind,Randomised, Crossover Trial of Two Botulinum Toxin Type A in Patients with Spasticity

Background

Botulinum toxin type A (btxA) is one of the main treatment choices for patients with spasticity. Prosigne® a new released botulinum toxin serotype A may have the same effectiveness as Botox® in focal dystonia. However, there are no randomized clinical trials comparing these formulations in spasticity treatment. The aim of our study was to compare the efficacy and safety of Prosigne® with Botox® in the treatment of spasticity.

Methodology/Principal Findings

We performed a double-blind, randomized, crossover study consisting of 57 patients with clinically meaningful spasticity. The patients were assessed at baseline, 4 and 12 weeks after Prosigne® or Botox® administration. The main outcomes were changes in the patients’ Modified Ashworth Scale (MAS), Functional Independence Measure (FIM) and Pediatric Evaluation of Disability Inventory (PEDI) scores and adverse effects related to the botulinum toxin. Both of the toxins were significantly effective in relieving the level of spasticity in adults and children. There were no significant differences found between the Prosigne® and Botox® treatments regarding their MAS, FIM and PEDI scores. Likewise, the incidence of adverse effects was similar between the two groups.

Conclusion

Our results suggest that Prosigne® and Botox® are both efficient and comparable with respect to their efficacy and safety for the three month treatment of spasticity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00819065","term_id":"NCT00819065"}}NCT00819065.     

Low Efficacy of Pegylated Interferon plus Ribavirin plus Nitazoxanide for HCV Genotype 4 and HIV Coinfection

Background

Nitazoxanide (NTZ) plus pegylated interferon and ribavirin (Peg-IFN/RBV) improved the sustained virological response (SVR) achieved with Peg-IFN/RBV in hepatitis C virus genotype 4 (HCV-4)-monoinfected patients. There are no data currently on the efficacy of Peg-IFN/RBV plus NTZ for human immunodeficiency virus (HIV)/HCV-4 coinfection. Therefore, the objectives of this clinical trial were to assess the efficacy and to evaluate the safety of Peg-IFN/RBV plus NTZ in HIV/HCV-4-coinfected patients.

Patients and Methods

This was an open-label, single arm, multicenter phase II pilot clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT01529073","term_id":"NCT01529073"}}NCT01529073) enrolling HIV-infected individuals with HCV-4 chronic infection, naïve to HCV therapy. Patients were treated with NTZ 500 mg bid for 4 weeks, followed by NTZ 500 mg bid plus Peg-IFN alpha-2b 1.5 μg/kg/week plus weight-adjusted RBV during 48 weeks. Analyses were done by intention-to-treat (ITT, missing = failure). A historical cohort of HIV/HCV-4-infected patients treated with Peg-IFN alpha-2b and RBV at the same area was used as control.

Results

Two (9.5%) of 21 patients included in the trial compared with 5 (21.7%) of 23 patients included in the historical cohort achieved SVR (SVR risk difference, -12.2%; 95% confidence interval, -33.2% to 8.8%; p = 0.416). Virological failure was due to lack of response in 13 (62%) individuals recruited in the trial. Two (9.5%) patients included in the trial and two (9.5%) individuals from the historical cohort discontinued permanently due to adverse events.

Conclusions

No increase in SVR was observed among HIV/HCV-4-coinfected patients receiving Peg-IFN/RBV plus NTZ compared with a historical cohort treated with Peg-IFN/RBV. Interruptions due to adverse events of Peg-IFN/RBV plus NTZ were similar to those of dual therapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01529073","term_id":"NCT01529073"}}NCT01529073     

Impact of Osteopathic Treatment on Pain in Adult Patients with Cystic Fibrosis – A Pilot Randomized Controlled Study

Background

Pain is a common complication in patients with cystic fibrosis (CF) and is associated with shorter survival. We evaluated the impact of osteopathic manipulative treatment (OMT) on pain in adults with CF.

Methods

A pilot multicenter randomized controlled trial was conducted with three parallel arms: OMT (group A, 16 patients), sham OMT (sham treatment, group B, 8 patients) and no treatment (group C, 8 patients). Medical investigators and patients were double-blind to treatment for groups A and B, who received OMT or sham OMT monthly for 6 months. Pain was rated as a composite of its intensity and duration over the previous month. The evolution of chest/back pain after 6 months was compared between group A and groups B+C combined (control group). The evolution of cervical pain, headache and quality of life (QOL) were similarly evaluated.

Results

There was no statistically significant difference between the treatment and control groups in the decrease of chest/back pain (difference = −2.20 IC95% [−4.81; 0.42], p = 0.098); also, group A did not differ from group B. However, chest/back pain decreased more in groups A (p = 0.002) and B (p = 0.006) than in group C. Cervical pain, headache and QOL scores did not differ between the treatment and control groups.

Conclusion

This pilot study demonstrated the feasibility of evaluating the efficacy of OMT to treat the pain of patients with CF. The lack of difference between the group treated with OMT and the control group may be due to the small number of patients included in this trial, which also precludes any definitive conclusion about the greater decrease of pain in patients receiving OMT or sham OMT than in those with no intervention.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01293019","term_id":"NCT01293019"}}NCT01293019     

A Randomized Pilot Trial of Remote Ischemic Preconditioning in Heart Failure with Reduced Ejection Fraction

Background

Remote ischemic preconditioning (RIPC) induced by transient limb ischemia confers multi-organ protection and improves exercise performance in the setting of tissue hypoxia. We aimed to evaluate the effect of RIPC on exercise capacity in heart failure patients.

Methods

We performed a randomized crossover trial of RIPC (4×5-minutes limb ischemia) compared to sham control in heart failure patients undergoing exercise testing. Patients were randomly allocated to either RIPC or sham prior to exercise, then crossed over and completed the alternate intervention with repeat testing. The primary outcome was peak VO2, RIPC versus sham. A mechanistic substudy was performed using dialysate from study patient blood samples obtained after sham and RIPC. This dialysate was used to test for a protective effect of RIPC in a mouse heart Langendorff model of infarction. Mouse heart infarct size with RIPC or sham dialysate exposure was also compared with historical control data.

Results

Twenty patients completed the study. RIPC was not associated with improvements in peak VO2 (15.6+/−4.2 vs 15.3+/−4.6 mL/kg/min; p = 0.53, sham and RIPC, respectively). In our Langendorff sub-study, infarct size was similar between RIPC and sham dialysate groups from our study patients, but was smaller than expected compared to healthy controls (29.0%, 27.9% [sham, RIPC] vs 51.2% [controls]. We observed less preconditioning among the subgroup of patients with increased exercise performance following RIPC (p<0.04).

Conclusion

In this pilot study of RIPC in heart failure patients, RIPC was not associated with improvements in exercise capacity overall. However, the degree of effect of RIPC may be inversely related to the degree of baseline preconditioning. These data provide the basis for a larger randomized trial to test the potential benefits of RIPC in patients with heart failure.

Trial Registration

ClinicalTrials.gov +++++{"type":"clinical-trial","attrs":{"text":"NCT01128790","term_id":"NCT01128790"}}NCT01128790