A Multicenter,Randomized, Controlled Trial of Osteopathic Manipulative Treatment on Preterms

BackgroundDespite some preliminary evidence, it is still largely unknown whether osteopathic manipulative treatment improves preterm clinical outcomes.ResultsA total of 695 newborns were randomly assigned to either the study group (n= 352) or the control group (n=343). A statistical significant difference was observed between the two groups for the primary outcome (13.8 and 17.5 days for the study and control group respectively, p<0.001, effect size: 0.31). Multivariate analysis showed a reduction of the length of stay of 3.9 days (95% CI -5.5 to -2.3, p<0.001). Furthermore, there were significant reductions with treatment as compared to usual care in cost (difference between study and control group: 1,586.01€; 95% CI 1,087.18 to 6,277.28; p<0.001) but not in daily weight gain. There were no complications associated to the intervention.ConclusionsOsteopathic treatment reduced significantly the number of days of hospitalization and is cost-effective on a large cohort of preterm infants.     

Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial

Background

Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%).

Methods and Findings

This randomized controlled trial included children (0.5–10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan–Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission.The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI −7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI −12, 1; p = 0.24). Delayed parasite clearance was associated with the ^N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms.A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner.

Conclusions

A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children.

Trial registration

Pan African Clinical Trials Registry PACTR201102000277177     

Neuronox versus BOTOX in the Treatment of Post-Stroke Upper Limb Spasticity: A Multicenter Randomized Controlled Trial

Background

Botulinum toxin type A is widely used for treating spasticity. Neuronox (Neu-BoNT/A), a newly manufactured botulinum toxin a, has not yet been investigated for its efficacy and safety in the treatment of post-stroke upper limb spasticity.

Objective

We evaluated the efficacy and safety of Neuronox (Neu-BoNT/A) compared with BOTOX (onabotulinum toxin A) for treating post-stroke upper limb spasticity.

Methods

In total, 196 stroke patients with moderate to severe upper limb spasticity were randomly assigned to either Neuronox or BOTOX intervention. The wrist flexors were mandatory and elbow, finger, and thumb flexors were optional muscles to be injected. Assessments were performed at baseline and 4, 8, and 12 weeks after the intervention. The primary outcome measure was the change from baseline of the Modified Ashworth Scale (MAS) at the wrist flexors at week 4. Secondary outcome measures included the change of MAS at each visit, response rate, Disability Assessment Scale (DAS), Carer Burden Scale, and Global Assessment of treatment benefit.

Results

Primary outcome measures were -1.39±0.79 and -1.56±0.81 in the Neuronox and BOTOX groups, respectively. The difference was within the noninferiority margin of 0.45 (95% upper limit=0.40). There were no significant differences between the groups in the secondary outcome and safety measures, except the change of the MAS at the elbow flexors at week 12 (-0.88±0.75 in the Neuronox group, -0.65±0.74 in the BOTOX group; P=0.0429). Both groups showed significant improvements in the MAS, DAS, and Carer Burden Scale at weeks 4, 8, and 12.

Conclusion

Neuronox showed equivalent efficacy and safety compared with BOTOX for treating post-stroke upper limb spasticity.

Trial Registration

ClinicalTrials.gov NCT01313767     

A Promising Approach to Effectively Reduce Cramp Susceptibility in Human Muscles: A Randomized,Controlled Clinical Trial

Background

To investigate if the cramp threshold frequency (CTF) can be altered by electrical muscle stimulation in a shortened position.

Methods

A total of 15 healthy male sport students were randomly allocated to an intervention (IG, n = 10) and a non-treatment control group (CG, n = 5). Calf muscles of both legs in the IG were stimulated equally twice a week over 6 weeks. The protocol was 3×5 s on, 10 s off, 150 µs impulse width, 30 Hz above the individual CTF, and was at 85% of the maximal tolerated stimulation energy. One leg was stimulated in a shortened position, inducing muscle cramps (CT), while the opposite leg was fixated in a neutral position at the ankle, hindering muscle cramps (nCT). CTF tests were performed prior to the first and 96 h after the 6^th (3 w) and 12^th (6 w) training session.

Results

After 3 w, the CTF had significantly (p<0.001) increased in CT calves from 23.3±5.7 Hz to 33.3±6.9 Hz, while it remained unchanged in nCT (pre: 23.6±5.7 Hz, mid: 22.3±3.5 Hz) and in both legs of the CG (pre: 21.8±3.2 Hz, mid: 22.0±2.7 Hz). Only CT saw further insignificant increases in the CTF. The applied stimulation energy (mA² • µs) positively correlated with the effect on the CTF (r = 0.92; p<0.001).

Conclusions

The present study may be useful for developing new non-pharmacological strategies to reduce cramp susceptibility.

Trial Registry

German Clinical Trials Register DRKS00005312     

Randomized,Single Blind,Controlled Trial to Evaluate the Prime-Boost Strategy for Pneumococcal Vaccination in Renal Transplant Recipients

Renal transplant recipients are at increased risk of developing invasive pneumococcal diseases but may have poor response to the 23-valent pneumococcal polysaccharide vaccine (PPV). It may be possible to enhance immunogenicity by priming with 7-valent pneumococcal conjugate vaccine (7vPnC) and boosting with PPV 1 year later. In a randomized single-blind, controlled study, adult recipients of renal transplants received either 7nPVC or PPV followed by PPV 1 year later. The vaccine response was defined as 2-fold increase in antibody concentration from baseline and an absolute post-vaccination values ≥1 µg/ml. The primary endpoint was vaccine response of the primed group (7vPnC/PPV) compared with single PPV vaccination. Antibody concentrations for 10 serotypes were measured at baseline, 8 weeks after first vaccination, before second vaccination, and 8 weeks after second vaccination. Of 320 screened patients, 80 patients were randomized and 62 completed the study. Revaccination with PPV achieved no significant increase of immune response in the 7vPnC/PPV group compared with the single PPV recipients A response to at least 1 serotype was seen in 77.1% of patients who received 7vPnC and 93.1% of patients who received PPV (P = 0.046). After second vaccination response to at least 1 serotype was seen in 87.5% patients of 7vPnC/PPV group and 87.1% patients of PPV group (non significant p). The median number of serotypes eliciting a response was 3.5 (95% CI 2.5–4.5) in the 7vPnC/PPV group versus 5 (95% CI 3.9–6.1) in the PPV group (non-significant p). Immunogenicity of pneumococcal vaccination was not enhanced by the prime–boost strategy compared with vaccination with PPV alone. Administration of a single dose of PPV should continue to be the standard of care for adult recipients of renal transplants.

Trial Registration

EudraCT 2007-004590-25.     

The Effectiveness of Pregabalin for Post-Tonsillectomy Pain Control: A Randomized Controlled Trial

BackgroundAlthough various analgesics have been used, postoperative pain remains one of the most troublesome aspects of tonsillectomy for patients.ObjectiveThe aim of the present study was to evaluate the effectiveness of premedication using pregabalin compared with placebo (diazepam) on postoperative pain control in patients undergoing tonsillectomy.MethodsForty-eight adult patients were randomly divided into a control group and a pregabalin group. Preoperatively, patients in the control group received 4 mg diazepam orally as placebo, whereas those in the pregabalin group received 300 mg pregabalin orally. All participants were provided with patient-controlled analgesia using fentanyl for 24 hours after surgery. Postoperative pain treatment included acetaminophen 650 mg three times daily for 8 postoperative days. The primary outcome measure was the total amount of patient-controlled fentanyl consumption after tonsillectomy. Secondary outcome measures were the number of injections of ketorolac tromethamine (each 30 mg) requested by patients, pain scores, overall satisfaction scores, drowsiness, nausea, dizziness, headache, and vomiting after the surgery. P < 0.05 was considered statistically significant.ResultsThe total amount of fentanyl demanded decreased significantly in the pregabalin group (P < 0.001). There were no significant differences in the number of ketorolac tromethamine injections, pain scores, overall satisfaction scores, drowsiness, nausea, dizziness, headache, and vomiting between the two groups.ConclusionAdministration of 300 mg pregabalin prior to tonsillectomy decreases fentanyl consumption compared with that after 4 mg diazepam, without an increased incidence of adverse effects.

Trial Registration

KCT0001215     

Efficacy and Safety of Transcutaneous Electrical Acupoint Stimulation to Treat Muscle Spasticity following Brain Injury: A Double-Blinded,Multicenter, Randomized Controlled Trial

ObjectiveThis study was aimed at evaluating the clinical efficacy and safety of transcutaneous electrical acupoint stimulation (TEAS) to treat muscle spasticity after brain injury (Chinese Clinical Trial Registry: ChiCTR-TRC-11001310).MethodsA total of 60 patients with muscle spasticity after brain injury were randomized to the following 3 groups: 100, 2, and 0 Hz (sham) TEAS. The acupoints Hegu (LI4)—Yuji (LU10) and Zusanli (ST36)—Chengshan (BL57) on the injured side were stimulated at 0, 2, or 100 Hz, 5 times per week for 4 weeks. The patients were followed up for 1 and 2 months after the treatments. The effects of the treatments on muscle spasticity at the wrist, thumb, the other 4 fingers, elbow, shoulder, knee, and ankle were evaluated by the Modified Ashworth Scale, and the effects on disability were assessed by the Disability Assessment Scale. The walking capability was evaluated by the Holden functional ambulation classification score. The overall performance was assessed by the Global Assessment Scale score and the improved Barthel Index. The safety of the treatments administered was also monitored.ResultsThe wrist spasticity was significantly reduced from baseline at weeks 2, 3, and 4 of treatment and at the 1- and 2-month follow-up visits in the 100 Hz group (P < 0.01). Compared with 2 Hz or sham TEAS, 100 Hz TEAS decreased wrist spasticity at weeks 2, 3, and 4 of treatment and 1 month after treatment (P < 0.001). The other endpoints were not affected by the treatments. No treatment-emergent adverse events were reported during treatments and follow-up visits.ConclusionsTEAS appears to be a safe and effective therapy to relieve muscle spasticity after brain injury, although large-scale studies are required to further verify the findings.

Trial Registration

Chinese Clinical Trial Registry ChiCTR-TRC-11001310 http://www.chictr.org     

Well-Loved Music Robustly Relieves Pain: A Randomized,Controlled Trial

Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly preferred music. A two-session experiment was performed with 48 healthy, pain experiment-naïve participants. In a first cohort, 36 were randomized into 3 treatment groups, including music enhanced with positive expectancy, non-musical sound enhanced with positive expectancy, and no expectancy enhancement. A separate replication cohort of 12 participants received only expectancy-enhanced music following the main experiment to verify the results of expectancy-manipulation on music. Primary outcome measures included the change in subjective pain ratings to calibrated experimental noxious heat stimuli, as well as changes in treatment expectations. Without conditioning, expectations were strongly in favor of music compared to non-musical sound. While measured expectations were enhanced by conditioning, this failed to affect either music or sound analgesia significantly. Strongly preferred music on its own was as pain relieving as conditioning-enhanced strongly preferred music, and more analgesic than enhanced sound. Our results demonstrate the pain-relieving power of personal music even over enhanced expectations.

Trial Information

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01835275","term_id":"NCT01835275"}}NCT01835275.     

Prophylactic Perioperative Sodium Bicarbonate to Prevent Acute Kidney Injury Following Open Heart Surgery: A Multicenter Double-Blinded Randomized Controlled Trial

Background

Preliminary evidence suggests a nephroprotective effect of urinary alkalinization in patients at risk of acute kidney injury. In this study, we tested whether prophylactic bicarbonate-based infusion reduces the incidence of acute kidney injury and tubular damage in patients undergoing open heart surgery.

Methods and Findings

In a multicenter, double-blinded (patients, clinical and research personnel), randomized controlled trial we enrolled 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass. At induction of anesthesia, patients received either 24 hours of intravenous infusion of sodium bicarbonate (5.1 mmol/kg) or sodium chloride (5.1 mmol/kg). The primary endpoint was the proportion of patients developing acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early under recommendation of the Data Safety and Monitoring Committee because interim analysis suggested likely lack of efficacy and possible harm. Groups were non-significantly different at baseline except that a greater proportion of patients in the sodium bicarbonate group (66/174 [38%]) presented with preoperative chronic kidney disease compared to control (44/176 [25%]; p = 0.009). Sodium bicarbonate increased urinary pH (from 6.0 to 7.5, p<0.001). More patients receiving bicarbonate (83/174 [47.7%]) developed acute kidney injury compared with control patients (64/176 [36.4%], odds ratio [OR] 1.60 [95% CI 1.04–2.45]; unadjusted p = 0.032). After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint (OR 1.45 [0.90–2.33], p = 0.120]). A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control (11/174 [6.3%] versus 3/176 [1.7%], OR 3.89 [1.07–14.2], p = 0.031).

Conclusions

Urinary alkalinization using sodium bicarbonate infusion was not found to reduce the incidence of acute kidney injury or attenuate tubular damage following open heart surgery; however, it was associated with a possible increase in mortality. On the basis of these findings we do not recommend the prophylactic use of sodium bicarbonate infusion to reduce the risk of acute kidney injury. Discontinuation of growing implementation of this therapy in this setting seems to be justified.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00672334","term_id":"NCT00672334"}}NCT00672334 Please see later in the article for the Editors'' Summary     

Active Video Game Exercise Training Improves the Clinical Control of Asthma in Children: Randomized Controlled Trial

Objective

The aim of the present study was to determine whether aerobic exercise involving an active video game system improved asthma control, airway inflammation and exercise capacity in children with moderate to severe asthma.

Design

A randomized, controlled, single-blinded clinical trial was carried out. Thirty-six children with moderate to severe asthma were randomly allocated to either a video game group (VGG; N = 20) or a treadmill group (TG; n = 16). Both groups completed an eight-week supervised program with two weekly 40-minute sessions. Pre-training and post-training evaluations involved the Asthma Control Questionnaire, exhaled nitric oxide levels (FeNO), maximum exercise testing (Bruce protocol) and lung function.

Results

No differences between the VGG and TG were found at the baseline. Improvements occurred in both groups with regard to asthma control and exercise capacity. Moreover, a significant reduction in FeNO was found in the VGG (p < 0.05). Although the mean energy expenditure at rest and during exercise training was similar for both groups, the maximum energy expenditure was higher in the VGG.

Conclusion

The present findings strongly suggest that aerobic training promoted by an active video game had a positive impact on children with asthma in terms of clinical control, improvementin their exercise capacity and a reductionin pulmonary inflammation.

Trial Registration

Clinicaltrials.gov NCT01438294     

Orthosis-Shaped Sandals Are as Efficacious as In-Shoe Orthoses and Better than Flat Sandals for Plantar Heel Pain: A Randomized Control Trial

Objective

To investigate efficacy of a contoured sandal being marketed for plantar heel pain with comparison to a flat flip-flop and contoured in-shoe insert/orthosis.

Method

150 volunteers aged 50 (SD: 12) years with plantar heel pain (>4 weeks) were enrolled after responding to advertisements and eligibility determined by telephone and at first visit. Participants were randomly allocated to receive commercially available contoured sandals (n = 49), flat flip-flops (n = 50) or over the counter, pre-fabricated full-length foot orthotics (n = 51). Primary outcomes were a 15-point Global Rating of Change scale (GROC: 1 = a very great deal worse, 15 = a very great deal better), 13 to 15 representing an improvement and the 20-item Lower Extremity Function Scale (LEFS) on which participants rate 20 common weight bearing activities and activities of daily living on a 5-point scale (0 = extreme difficulty, 4 = no difficulty). Secondary outcomes were worst level of heel pain in the preceding week, and the foot and ankle ability measure. Outcomes were collected blind to allocation. Analyses were done on an intention to treat basis with 12 weeks being the primary outcome time of interest.

Results

The contoured sandal was 68% more likely to report improvement in terms of GROC compared to flat flip-flop. On the LEFS the contoured sandal was 61% more likely than flat flip-flop to report improvement. The secondary outcomes in the main reflected the primary outcomes, and there were no differences between contoured sandal and shoe insert.

Conclusions and Relevance

Physicians can have confidence in supporting a patient''s decision to wear contoured sandals or in-shoe orthoses as one of the first and simple strategies to manage their heel pain.

Trial Registration

The Australian New Zealand Clinical Trials Registry ACTRN12612000463875     

Supported Telemonitoring and Glycemic Control in People with Type 2 Diabetes: The Telescot Diabetes Pragmatic Multicenter Randomized Controlled Trial

BackgroundSelf-monitoring of blood glucose among people with type 2 diabetes not treated with insulin does not appear to be effective in improving glycemic control. We investigated whether health professional review of telemetrically transmitted self-monitored glucose results in improved glycemic control in people with poorly controlled type 2 diabetes.ConclusionsSupported telemonitoring resulted in clinically important improvements in control of glycaemia in patients with type 2 diabetes in family practice. Current Controlled Trials, registration number ISRCTN71674628.

Trial Registration

Current Controlled Trials ISRCTN 71674628     

Training Medical Specialists to Communicate Better with Patients with Medically Unexplained Physical Symptoms (MUPS). A Randomized,Controlled Trial

Background

Patients with medically unexplained physical symptoms (MUPS) are prevalent 25–50% in general and specialist care. Medical specialists and residents often find patients without underlying pathology difficult to deal with, whereas patients sometimes don’t feel understood. We developed an evidence-based communication training, aimed to improve specialists’ interviewing, information-giving and planning skills in MUPS consultations, and tested its effectiveness.

Methods

The intervention group in this multi-center randomized controlled trial received a 14-hour training program to which experiential learning and feedback were essential. Using techniques from Cognitive Behavioral Therapy, they were stimulated to seek interrelating factors (symptoms, cognitions, emotions, behavior, and social environment) that reinforced a patient’s symptoms. They were taught to explain MUPS understandably, reassure patients effectively and avoid unnecessary diagnostic testing. Before and after the intervention training, specialists videotaped a total of six consultations with different MUPS patients. These were evaluated to assess doctors’ MUPS-focused communicating skills using an adapted version of the Four Habit Coding Scheme on five-point Likert scales. Participants evaluated the training by self-report on three-point Likert scales. Doctors in the control group received training after completion of the study.

Results

123 doctors (40% specialists, 60% residents) and 478 MUPS patients from 11 specialties were included; 98 doctors completed the study (80%) and 449 videotaped consultations were assessed. Trained doctors interviewed patients more effectively than untrained ones (p < 0.001), summarized information in a more patient-centered way (p = 0.001), and better explained MUPS and the role of perpetuating factors (p < 0.05). No effects on planning skills were found. On a 3-point scale the training was evaluated with 2.79.

Conclusion

MUPS-focused communication training increases the interviewing and information-giving skills of medical specialists. We recommend that the training is incorporated in postgraduate education for medical specialists and residents who frequently encounter patients with MUPS.

Trial Registration

Dutch Trial Registration NTR2612     

Effects of Two Chinese Herbal Formulae for the Treatment of Moderate to Severe Stable Chronic Obstructive Pulmonary Disease: A Multicenter,Double-Blind,Randomized Controlled Trial

Objective

The study aims to evaluate the efficacy and safety of two Chinese herbal formulae for the treatment of stable COPD.

Methods

A multicenter, double-blind, double-dummy, and randomized controlled trial (RCT) was conducted. All groups were treated with additional conventional medicines. There were a 6-month treatment and a 12-month follow-up for 5 times. Primary outcomes included lung function test, exacerbation frequency, score of SGRQ. Second outcomes consisted of 6MWD, BODE index, psychological field score, inflammatory factors and cortisol.

Results

A total of 331 patients were randomly divided into two active treatment groups (Bushen Yiqi (BY) granule group, n = 109; Bushen Fangchuan (BF) tablet group, n = 109) and a placebo group (n = 113). Finally 262 patients completed the study. BY granule & BF tablet increased the values of VC, FEV₁ (%) and FEV₁/FVC (%), compared with placebo. BY granule improved PEF. Both treatments reduced acute exacerbation frequency (P = 0.067), BODE index and psychological field score, while improved 6MWD. In terms of descent rang of SGRQ score, both treatments increased (P = 0.01). Both treatments decreased inflammatory cytokines, such as IL-8, and IL-17(P = 0.0219). BY granule obviously descended IL-17(P<0.05), IL-1β (P = 0.05), IL-6, compared with placebo. They improved the level of IL-10 and cortisol. BY granule raised cortisol (P = 0.07) and decreased TNF-α. Both treatments slightly descended TGF-β1. In terms of safety, subject compliance and drug combination, there were no differences (P>0.05) among three groups.

Conclusions

BY granule and BF tablet were positively effective for the treatment of COPD, and the former performed better in general.

Trial Registration

Chinese Clinical Trial Register center ChiCTR-TRC-09000530     

Therapeutic Vaccination with TNF-Kinoid in TNF Antagonist-Resistant Rheumatoid Arthritis: A Phase II Randomized,Controlled Clinical Trial

Objectives

Active immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA.

Methods

This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection.

Results

The highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not.

Conclusions

TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement.

Trial Registration

ClinicalTrials.gov NCT01040715     

吗啡皮下自控镇痛泵治疗难治性癌痛的前瞻性多中心随机对照研究

摘要 目的：观察吗啡皮下自控镇痛泵治疗难治性癌痛的临床疗效。方法：采用前瞻性多中心随机对照研究,应用治疗方法分为试验组和对照组,其中试验组使用皮下自控阵痛泵给药,对照组口服吗啡片剂,5 d为一疗程,共计观察3疗程。观察两组患者治疗后疼痛积分改善情况;每疗程吗啡日均用量;疼痛起效时间、最佳缓解时间;镇痛维持时间及剂量稳定天数、爆发痛情况;生活质量改善及不良反应发生率;疗程费用情况。结果：两组患者数字疼痛评分法(numerical rating scale,NRS)评分在治疗后均较镇痛前显著降低（P＜0.05）;在吗啡用量比较方面,试验组吗啡用量显著低于对照组同期用量;试验组在疼痛缓解时间、疼痛最佳缓解时间方面均显著优于对照组;治疗期间试验组平均镇痛维持时间明显长于对照组（P＜0.05）;两组患者治疗后体力状况分析标准(performance status,PS)评分较治疗前显著改善;试验组便秘、嗜睡不良反应发生率显著低于对照组（P＜0.05）。试验组每疗程费用明显低于对照组,具有明显经济优势。结论：吗啡皮下自控镇痛泵给药方式控制难治性癌痛临床疗效确切,止痛效果明显。与对照组比较,疼痛起效时间短,疗程较吗啡用量少,不良反应发生率低,改善了患者生活质量,且减轻了患者经济压力。