Double-dummy Trial Research Articles

Efficacy and Tolerability of Celecoxib versus Naproxen in Patients with Osteoarthritis of the Knee: A Randomized, Double-Blind, Double-Dummy Trial

To assess the efficacy and tolerability of celecoxib versus naproxen in patients with osteoarthritis (OA) of the knee. This 6-month, randomized, double-blind, double-dummy trial was conducted at 47 centres in the USA. Patients with OA of the knee were randomized to receive 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily. The primary endpoint was defined as a 20% improvement from baseline to 6 months in Western Ontario and McMaster Universities (WOMAC) OA total score. A total of 586 out of 589 randomized patients received at least one dose of celecoxib (n=294) or naproxen (n=292). The primary endpoint (6-month response rate) was achieved by 52.7% and 49.7% of patients in the celecoxib and naproxen treatment groups, respectively. Significantly fewer discontinuations due to gastrointestinal adverse events occurred in patients receiving celecoxib than in those receiving naproxen (4.1% versus 15.1%, respectively). Over the 6month study period, celecoxib provided similar improvements in OA symptoms to naproxen. In addition, celecoxib provided better upper gastrointestinal tolerability than naproxen.

Efficacy and safety of acarbose chewable tablet in patients with type 2 diabetes: a multicentre, randomized, double‐blinded, double‐dummy positive controlled trial

To evaluate the effect and safety of HbA1c and glycemic control of acarbose chewable tablets in patients with type 2 diabetic. A multicentre, randomized, double-blinded, double-dummy, positive controlled clinical trial was conducted. Two hundred thirty-four Chinese patients with type 2 diabetic were enrolled in eight clinical centres, who were divided randomly into the acarbose chewable tablet group (experimental group, n = 116) and the acarbose treatment group (control group, n = 118). Two hundred seven patients (88.5%) took part in the 12-week trial. At the beginning and end of the clinical trial, HbA1c and blood glucose as well as safety indexes were measured. After the treatment, the level of finger two-hour postprandial blood glucose (PPBG) was decreased 4.15 mmol/L (26.82%) and 3.54 mmol/L (22.77%), respectively, in the experiment group and the control group. The levels of venous two-hour PPBG in the experiment group and the control group were decreased 4.04 mmol/L (25.38%) and 2.75 mmol/L (17.26%), respectively, with the means of HbA1c lowering 11.67% and 12.44%, respectively. Fasting blood glucose (FBG) also was reduced significantly in both groups. Patients in both groups showed obvious weight reduction (P < 0.0001). There were no significant differences in the incidence of adverse events between the two groups. In summary, acarbose chewable tablets have a definite curative effect in treating type 2 diabetic patients as HbA1c and blood glucose levels decreased significantly after the 12-week treatment.

OA07.03. Randomized, double-blind, double-dummy trial of myrrh, chamomile, coffee charcoal compared to mesalazine in maintaining remission in ulcerative colitis

Methods A total of 96 patients (51 female) with UC in remission (not longer than 12 months) were included in a randomized, double-blind, double-dummy, multicenter, non inferiority study comparing mesalazine 500 mg (3x1/d) to 100mg myrrh, 70mg chamomile extract and 50mg coffee charcoal (3 x 4/d) over a time period of 12 months. As primary outcome criterion, non-inferiority of the herbal preparation was defined and accepted, if the difference in the colitis activity index (Colitis Activity Index CAI Rachmilewitz) (calculated at six time points during the 12 month interval) averaged over all visits was ≤ 1 point. Furthermore, relapse rates, relapse-free times, safety, a comprehensive activity index (CAI, CRP and fecal Lactoferrin, Calprotectin and PMN-Elastasis), an endoscopic activity index and Health-related Quality of life (HrQoL) were assessed. Peripheral CD4+CD25+ reg T-cells were investigated in a subgroup at each time point and during a flare.

Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: Study protocol for a randomised controlled trial

BackgroundChildren with sickle cell disease (SCD) frequently and unpredictably present to the emergency department (ED) with pain. The painful event is the hallmark acute clinical manifestation of SCD, characterised by sudden onset and is usually bony in origin. This study aims to establish if 1.5mcg/kg of intranasal fentanyl (INF; administered via a Mucosal Atomiser Device, MAD™) is non-inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain.Methods/designThis study is a randomised,double-blind, double-dummy active control trial of children (weighing more than 10 kg) between 1 year and 21 years of age with severe painful sickle cell crisis. Severe pain is defined as rated seven or greater on a 0 to 10 age-appropriate numeric pain scale or equivalent. The trial will be conducted in a single tertiary urban paediatric ED in Dublin, Ireland. Each patient will receive a single active agent and a single placebo via the intravenous and intranasal routes. All clinical and research staff, patients and parents will be blinded to the treatment allocation. The primary endpoint is severity of pain scored at 10 min from administration of the study medications. Secondary endpoints include pain severity measured at 0, 5, 15, 20, 30, 60 and 120 min after the administration of analgesia, proportion of patients requiring rescue analgesia and incidence of adverse events. The trial ends at 120 min after the administration of the study drugs. A clinically meaningful difference in validated pain scores has been defined as 13 mm. Setting the permitted threshold to 50% of this limit (6 mm) and assuming both treatments are on average equal, a sample size of 30 patients (15 per group) will provide at least 80% power to demonstrate that INF is non-inferior to IV morphine with a level of significance of 0.05.DiscussionThis clinical trial will inform of the role of INF 1.5mcg/kg via MAD in the acute treatment of severe painful sickle cell crisis in children in the ED setting.Trial registrationCurrent Controlled Trials ISRCTN67469672 and EudraCT no. 2011-005161-20

Association between transitory increase in PTH following denosumab administration and reduced intracortical porosity is a distinctive attribute of denosumab therapy

Two processes largely determine the impact of an antiresorptive on bone mass and structure: its direct and indirect effects on the volumes of bone resorbed and deposited by each bone remodeling unit (BMU) and the numberof BMUs inhibited in both the trabecular and cortical compartments. Denosumab (DMAb) markedly inhibits the birth rate of new BMUs and rapidly reduces bone resorption by existing BMUs following administration. This acute reduction in remodeling is accompanied bya transitory increase in circulating endogenous PTH, which has the theoretical potential to increase osteoblast longevity and/or activity. We tested the hypothesis that the direct effect of DMAb on inhibition of resorption, and the possible indirect effect on bone formationmediated by an increase in PTH in the face of inhibited osteoclast activity by the BMU,would be associated with a reduction in cortical porosity in postmenopausal women. In this double-blind, double-dummy trial, 247 postmenopausal women with mean (SD) age 60.6 (5.4) yrs and low BMD were randomly assigned to DMAb 60 mg Q6M (N=83), alendronate (ALN) 70 mg QW (N=82) or placebo (Pbo; N=82). PTH was measured at baseline (BL), week 1 and months 1, 3, 6, 6.25, 7, 9 and 12. Area under the curve (AUC) for PTH was derived from the change from BL for each subject. Porosity was evaluated in the compact-appearing cortex of the distal radius at BL and mo 12 by HR-pQCT. Associations between PTH AUC and change in porosity were evaluated. Transitory increases in PTHwere seen in the DMAb and ALN, but not Pbo, groups. The increase in PTH was larger following DMAb than ALN (Pb0.05) and was observed after each DMAb dose. By 12 mo, porosity in the radius increased in the Pbo group (+5.2%), increased less in the ALN group (+2.9%) and was reduced by DMAb (−3.0%). In the Pbo andALN groups, porosity increasedwith increasing PTH,whilewith DMAb, it decreased as PTH increased. These relationships were maintained after adjusting for BL remodeling. Thus, DMAb partly reverses microarchitectural deterioration. The predominant mechanism is the direct major reduction of bone remodeling intensity, with perhaps an indirect effect of transiently increasing PTH with an associated increase in bone formation positively influencing BMU balance. This is a distinct attribute of DMAb administration since the increase in endogenous PTH, expected to be catabolic to bone, occurs when osteoclastic resorption is fully inhibited by DMAb.

Gaviscon® vs. omeprazole in symptomatic treatment of moderate gastroesophageal reflux. a direct comparative randomised trial

BackgroundMedical management of GERD mainly uses proton pump inhibitors. Alginates also have proven efficacy. The aim of this trial was to compare short-term efficacy of an alginate (Gaviscon®, 4 × 10 mL/day) and omeprazole (20 mg/day) on GERD symptoms in general practice.MethodsA 14-day multicentre randomised double-blind double-dummy non-inferiority trial compared Gaviscon® (4 × 10 mL/day) and omeprazole (20 mg/day) in patients with 2-6 day heartburn episodes weekly without alarm signals. The primary outcome was the mean time to onset of the first 24-h heartburn-free period after initial dosing. Secondary outcomes were the proportion of patients without heartburn by D7, pain relief by D7, and reduction in pain intensity by D7 and D14.Results278 patients were recruited; 120 were included in the Gaviscon® group and 121 in the omeprazole group for the per protocol non-inferiority analysis. The mean time to onset of the first 24-h heartburn-free period after initial dosing was 2.0 (± 2.2) days for Gaviscon® and 2.0 (± 2.3) days for omeprazole (p = 0.93); mean intergroup difference was 0.01 ± 1.55 days (95% CI = -0.41 to 0.43): i.e., less than the lower limit of the 95% CI of -0.5 days predetermined to demonstrate non-inferiority. The mean number of heartburn-free days by D7 was significantly greater in the omeprazole group: 3.7 ± 2.3 days vs. 3.1 ± 2.1 (p = 0.02). On D7, overall quality of pain relief was slightly in favour of omeprazole (p = 0.049). There was no significant difference in the reduction in pain intensity between groups by D7 (p = 0.11) or D14 (p = 0.08). Tolerance and safety were good and comparable in both groups.ConclusionGaviscon® was non-inferior to omeprazole in achieving a 24-h heartburn-free period in moderate episodic heartburn, and is a relevant effective alternative treatment in moderate GERD in primary care.Trial registrationISRCTN62203233.

P281 Randomized, double-blind, double-dummy trial of myrrh, camomile and coffee charcoal compared to mesalazine in maintaining remission in ulcerative colitis

P281 Randomized, double-blind, double-dummy trial of myrrh, camomile and coffee charcoal compared to mesalazine in maintaining remission in ulcerative colitis

Comparison of a Chinese Herbal Medicine (CCH1) and Lactulose as First-Line Treatment of Constipation in Long-Term Care: A Randomized, Double-Blind, Double-Dummy, and Placebo-Controlled Trial

Many institutionalized patients and their healthcare providers are dissatisfied with current laxative therapy. This study compared therapeutic efficacy, safety, and laxative cost of an herbal formula (CCH1) and lactulose for long stay patients with constipation. In this double-blind, double-dummy, and placebo-controlled trial, we randomized 93 residents with chronic constipation from two long-term care facilities in Taiwan to receive either CCH1 with lactulose placebo or CCH1 placebo with lactulose for 8 weeks, then followed up for 4 weeks without study medication. Both treatments were effective and well tolerated for patients, but CCH1 produced more spontaneous bowel movements, less rectal treatments, less amount of rescue laxative, and lower laxative cost than lactulose during treatment. No significant differences were found in stool consistency, stool amount, global assessment, and safety concerns. In conclusion, our results suggest that CCH1 may have better efficacy and could be used as an alternative option to lactulose in the treatment of constipation in long-term care.

Sensitivity of gait parameters to the effects of anti‐inflammatory and opioid treatments in knee osteoarthritis patients

The study aim was to address the need for objective markers of pain-modifying interventions by testing the hypothesis that selective gait measures of knee joint loading can distinguish differences between non-steroidal anti-inflammatory (NSAID), analgesic treatment (opioid-receptor agonist), and placebo in patients medial knee osteoarthritis (OA). A randomized, single-blind washout, double-blind treatment, double-dummy cross-over trial using three treatment arms placebo, opioid (Oxycodone), and NSAID (Celecoxib) in medial compartment knee OA patients. Six patients with Kellgren-Lawrence radiographic severity grades of 2 or 3 completed six testing sessions (gait and pain assessment) at 2-week intervals. A significant increase was found in the knee total reaction moment and vertical ground reaction force (GRF) for Celecoxib compared to placebo (p=0.005, p=0.003), but not for Oxycodone compared to placebo (p=0.20, p=0.27) treatments. Walking speed was significantly higher for the Celecoxib and Oxycodone compared to placebo treatment (p=0.041 and p=0.031, respectively). Self-reported function (WOMAC scores) was not different among treatments (p>0.05). The changes in total reaction moments and GRFs for only the NSAID suggest that greater increases in joint loading occurs when joint inflammation is treated in addition to pain. The total knee reaction moment, representing the magnitude of the extrinsic moment, appears to be a sensitive marker, more so than self-reported metrics, for evaluating knee OA treatment effects.

P4-13-01: Pain Severity and Analgesic Use Associated with Skeletal-Related Events in Patients with Advanced Breast Cancer and Bone Metastases.

Abstract Background: Skeletal-related events (SREs), which include pathologic fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC), occur frequently in patients with bone metastases and can lead to debilitating clinical consequences such as functional impairment and bone pain. Denosumab (XGEVA®) is a fully human monoclonal antibody against RANKL, shown to be superior to zoledronic acid (ZA; Zometa®) for the prevention of SREs in patients with solid tumors. Denosumab also delayed the onset of moderate or severe pain compared with ZA. The pain severity and analgesic use associated with each type of SRE were assessed in patients with advanced breast cancer and bone metastases. Methods: Eligible patients received denosumab 120 mg SC or ZA 4 mg (adjusted for renal function) IV every 4 weeks in a randomized, multinational, double-blind, double-dummy trial. Patient-reported pain was assessed with the Brief Pain Inventory (BPI; 0 no pain to 10 severe pain) at baseline (BL) and at each monthly visit. Opioid and non-opioid analgesic use was recorded and scored using the Analgesic Quantification Algorithm (AQA; 0 no analgesic use to 7 &amp;gt; 600mg oral morphine equivalent/day). Data from the two treatment arms were pooled for this analysis. Pain and analgesic use were evaluated from 6 months prior to and 6 months after the first on-study SRE for each patient. The comparator group included patients without an SRE and was centered at the median time from randomization to first SRE by SRE type, with corresponding 12 month assessments. The proportion of patients with moderate/severe pain (BPI worst pain score &amp;gt; 4) and proportion of patients shifting from no/low analgesic use (AQA ≤ 2) at baseline to strong opioid use (AQA ≥ 3) were reported by month and by SRE type, and are summarized by mean relative change (%) across the time period. Results: In total, 687 patients with first on-study SRE occurrences (PF=450, RB=201, SCC=16, SB=20) were analyzed. A similar proportion of patients with and without a PF had moderate/severe pain, but a higher proportion of patients with a PF shifted from no/low analgesic use to strong opioid use (mean relative increase 80%). Starting 3 months prior to the event, more patients with RB than those without had moderate/severe pain (27% mean relative increase) and shifted from no/low analgesic use to strong opioid use (mean relative increase 269%). Similar pain and analgesic use patterns were noted for patients with SCC (mean relative increase in pain: 63%; in AQA shift: 913%). More patients with SB than those without had moderate/severe pain in the 6 months leading on to SB (mean relative increase 51%). The difference was attenuated after SB, but during this time a much higher proportion of patients with SB shifted from no/mild opioid use to strong opioid use (mean relative increase 220%). Discussion: SREs are associated with increased pain severity and analgesic use in patients with advanced breast cancer and bone metastasis. Patterns of pain severity and analgesic use differed by SRE type. Effective treatments to prevent SREs can decrease pain and the need for treatment with opioid analgesics. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-13-01.

P3-16-07: Denosumab in Patients with Breast Cancer and Bone Metastases Previously Treated with Zoledronic Acid or Denosumab: Results from the 2-Year Open-Label Extension Treatment Phase of a Pivotal Phase 3 Study.

Abstract Background Primary results from a phase 3, randomized, double-blind double-dummy trial showed that compared with zoledronic acid (ZA), denosumab reduced the risk of developing a first on-study SRE by 18% (hazard ratio, 0.82; 95% CI 0.71 to 0.95; P = 0.01), and the risk of multiple SREs by 23% (rate ratio, 0.77; 95% CI 0.66 to 0.89; P = 0.001) in patients with breast cancer and bone metastases. Based on superior efficacy and favorable safety data from the study's primary analysis (Stopeck et al, 2010), all patients who remained on treatment were offered open-label denosumab in a prespecified 2-year extension treatment phase. Materials and Methods: A total of 2046 patients with breast cancer and bone metastasis were randomized to receive either subcutaneous (SC) denosumab 120 mg and intravenous (IV) placebo or IV ZA 4 mg (adjusted for renal function) and SC placebo Q4W in the double-blinded treatment phase. Patients who completed the double-blinded treatment phase were offered open-label denosumab Q4W for up to 2 years from the start of the open-label treatment phase. Patients who did not participate in the open-label treatment were followed for survival every 12 weeks for up to 2 years after their last dose of investigational product in the double-blinded treatment phase. Results: Of the 752 patients who completed the double-blinded treatment phase, 667 (89%) patients entered the open-label treatment phase: 325 (48.7%) initially randomized to the denosumab group (DD) and 342 (51.3%) to the ZA group in the double-blinded treatment phase (ZD). Demographics were comparable between groups. The total median (Q1, Q3) cumulative denosumab exposure (including double-blinded and open-label treatment phases) for DD patients was 19.3 months (9.2, 32.2) (range 0.9−59.8 months). Adverse events (AEs) were comparable between groups (n = 283/318 [89%] for DD patients; n = 303/334 [91%] ZD patients). An additional 20 patients in the DD group and 18 patients in the ZD group reported osteonecrosis of the jaw, resulting in a cumulative incidence of 4.7% for DD patients and 3.5% for ZD patients for the entire study duration of 5 years. Hypocalcemia AEs during the open-label treatment phase were comparable between groups (n = 12 DD; n = 9 ZD). The most common AEs were nausea, fatigue, and back pain. Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between groups over the entire study: median 34.4 months (95% CI 31.5 to 39.3) for DD patients, 34.2 months (95% CI 31.0 to 37.6) for ZD patients. Conclusion: A two-year open-label extension treatment phase confirmed the long-term safety profile of denosumab in these breast cancer patients with bone metastases who continued receiving denosumab for up to 5 years or who switched from ZA to denosumab. No new safety signals were observed with up to 5 years of monthly denosumab therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-07.

The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures

The effect of teriparatide and risedronate on back pain was tested, and there was no difference in the proportion of patients experiencing a reduction in back pain between groups after 6 or 18months. Patients receiving teriparatide had greater increases in bone mineral density and had fewer vertebral fractures. This study aimed to understand the effect of teriparatide in reducing back pain in patients with prevalent back pain and vertebral fracture compared to risedronate. In an 18-month randomized, double-blind, double-dummy trial, we investigated the effects of teriparatide (20μg/day) vs. risedronate (35mg/week) in postmenopausal women with back pain likely due to vertebral fracture. The primary objective was to compare the proportion of subjects reporting ≥30% reduction in worst back pain severity from baseline to 6months as assessed by a numeric rating scale in each treatment group. Pre-specified secondary and exploratory outcomes included assessments of average and worst back pain at additional time points, disability and quality of life, bone mineral density, incidence of fractures, and safety. At 6months, 59% of teriparatide and 57% of risedronate patients reported ≥30% reduction in worst back pain and there were no differences between groups in the proportion of patients experiencing reduction in worst or average back pain at any time point, disability, or quality of life. There was a greater increase from baseline in bone mineral density at the lumbar spine (p = 0.001) and femoral neck (p = 0.02) with teriparatide compared to risedronate and a lower incidence of vertebral fractures at 18months (4% teriparatide and 9% risedronate; p = 0.01). Vertebral fractures were less severe (p = 0.04) in the teriparatide group. There was no difference in the overall incidence of adverse events. Although there were no differences in back pain-related endpoints, patients receiving teriparatide had greater skeletal benefit than those receiving risedronate.

Pramipexole versus dual release levodopa in restless legs syndrome: a double blind, randomised, cross-over trial

To compare efficacy and safety of the dopamine agonist pramipexole (PPX) versus reference treatment with dual release levodopa/benserazide (L/B) in de novo patients with restless legs syndrome (RLS). A total of 39 men and women between 25 and 85 years old, fulfilling all clinical criteria for diagnosis of idiopathic RLS, previously untreated, participated. The study was performed as a randomised, double-blind, double-dummy crossover trial with two treatment periods of four weeks and took place in six Swiss certified sleep-centres. Interventions were PPX 0.25-0.75 mg and dual-release L/B 125-375 mg. The primary outcome measure was the frequency of periodic limb movements while in bed (PLM index, PLMI). Secondary endpoints included the changes in patient ratings on the International RLS Study Group Rating Scale (IRLS). Both pramipexole and dual-release L/B were effective in reducing PLM and RLS symptoms. Mean PLMI reduction was -11.5 for PPX and -7.7 for L/B (baseline 21.1 and 21.5), and the mean IRLS score reduction was -7.2 and -4.0 (baseline 20.8 and 21.1). In patients with an IRLS score >20 (38%), a significantly (p = 0.047) higher PLMI reduction for PPX (-8.5), as compared to L/B (-4.3), was found. A higher incidence of "augmentations" and "involuntary movements" for L/B, and "nausea or vomiting" and "hypotension with dizziness" for PPX treatment were noted as adverse effects. This study showed comparable effects of PPX versus dual-release L/B for short-term treatment of de novo patients with mild to moderate RLS.

A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism (RE-COVER II)

Abstract 205 Background:Dabigatran has been compared with warfarin for treatment of acute venous thromboembolism in one previous trial (RE-COVER). Based on the low rate of the primary outcome as the RE-COVER study was running, we undertook this replica study to confirm the results of RE-COVER, and to allow for more rigorous sub-group analyses. Methods:In a randomized, double-blind, double-dummy trial of 2568 patients with acute VTE, treated with low molecular weight or unfractionated heparin for 5 to 11 days, we compared dabigatran, 150 mg twice daily, with warfarin, dose-adjusted to an International Normalized Ratio of 2.0 and 3.0, each given for 6 months. Primary outcome was recurrent symptomatic, objectively confirmed venous thromboembolism and deaths related to venous thromboembolism during 6 months. Safety endpoints included bleeding events, acute coronary syndrome, elevated liver function tests, and adverse events. Results:Of 1279 patients randomized to dabigatran, 30 (2.4%) had recurrent VTE compared with 28 (2.2%) of 1289 patients randomized to warfarin; risk difference 0.2% (95% confidence interval [CI], −1.0 to 1.5); p<0.0001 for the pre-specified non-inferiority margin. The hazard ratio for dabigatran was 1.08 (95% CI, 0.64 to 1.80). Major bleeding occurred in 15 patients treated with dabigatran and 22 patients treated with warfarin (hazard ratio 0.69; 95% CI, 0.36 to 1.32) and any bleeding occurred in 200 versus 285 patients, respectively (hazard ratio 0.67, 95% CI, 0.56 to 0.81). The frequency of reported ACS events was less than 1% in the trial, with more cases in the dabigatran treatment group than those treated with warfarin. There were 25 deaths during each treatment, and serious adverse events were similar in the two groups. Analysis of outcomes based on demographic characteristics showed consistency of effects for both safety and efficacy. This included the analysis based on Asian race, which had been limited in RE-COVER. There were 537 Asian patients in RE-COVER II compared to only 65 in RE-COVER. The event rates of recurrent VTE and of any bleeding were similar in Asians and non-Asians. Conclusion:The study confirms that the efficacy of dabigatran is non-inferior to warfarin in the treatment of acute VTE and with a lower risk for bleeding. The safety of dabigatran is similar in the Asian population compared with non-Asians. Disclosures:Off Label Use: dabigatran for treatment of venous thromboembolism. Christiansen:Boehringer Ingelheim: Employment. Schnee:Boehringer Ingelheim: Employment.

Impact of treatment approach on maternal and neonatal outcome in pregnant opioid‐maintained women

The objective of this study is to compare maternal and neonatal outcome of opioid-dependent women maintained on buprenorphine or methadone throughout pregnancy in a randomized double-blind double-dummy clinical trial (CT) with a comparison group undergoing a structured standard protocol (SP) at the Medical University of Vienna, Austria. One hundred and fourteen subjects were included in the analysis, with 77 in SP (n = 51 methadone, n = 26 buprenorphine), and 37 in CT (n = 19 methadone, n = 18 buprenorphine), comparing maternal concomitant consumption during third trimester, demographic birth data, duration of treatment for neonatal abstinence syndrome (NAS), morphine dose for NAS treatment and length of hospital stay (LOS). Both study groups yielded healthy neonates with no significant demographic differences and equivalently low rates of positive maternal urine toxicologies. However, NAS parameters were significantly better in CT regarding total medication dose administered to neonates (p = 0.014) and LOS (p = 0.015). Superior results were achieved in buprenorphine compared with methadone-exposed neonates regarding gestational age at birth (p = 0.003), birth weight (p = 0.011), total morphine dose administered (p = 0.008), NAS treatment duration (p = 0.008) and LOS (p = 0.001). Comparably favorable outcome for mothers and infants and efficacy and safety of opioid medications were shown in both treatment approaches. Neonatal care could benefit from transferring successful CT procedures into clinical practice.

Cranberries vs Antibiotics to Prevent Urinary Tract Infections

The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in cranberries to prevent recurrent urinary tract infections (UTIs). In a double-blind, double-dummy noninferiority trial, 221 premenopausal women with recurrent UTIs were randomized to 12-month prophylaxis use of trimethoprim-sulfamethoxazole (TMP-SMX), 480 mg once daily, or cranberry capsules, 500 mg twice daily. Primary end points were the mean number of symptomatic UTIs over 12 months, the proportion of patients with at least 1 symptomatic UTI, the median time to first UTI, and development of antibiotic resistance in indigenous Escherichia coli. After 12 months, the mean number of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (4.0 vs 1.8; P = .02), and the proportion of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (78.2% vs 71.1%). Median time to the first symptomatic UTI was 4 months for the cranberry and 8 months for the TMP-SMX group. After 1 month, in the cranberry group, 23.7% of fecal and 28.1% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant, whereas in the TMP-SMX group, 86.3% of fecal and 90.5% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant. Similarly, we found increased resistance rates for trimethoprim, amoxicillin, and ciprofloxacin in these E coli isolates after 1 month in the TMP-SMX group. After discontinuation of TMP-SMX, resistance reached baseline levels after 3 months. Antibiotic resistance did not increase in the cranberry group. Cranberries and TMP-SMX were equally well tolerated. In premenopausal women, TMP-SMX, 480 mg once daily, is more effective than cranberry capsules, 500 mg twice daily, to prevent recurrent UTIs, at the expense of emerging antibiotic resistance. isrctn.org Identifier: ISRCTN50717094.

A traditional Chinese medicine versus Western combination therapy in the treatment of rheumatoid arthritis: two-stage study protocol for a randomized controlled trial

BackgroundThe common randomized controlled trial design has distinct limitations when applied to Chinese medicine, because Chinese medicine identifies and treats 'Chinese medicine patterns' rather than diagnosed diseases. Chinese medicine patterns are a group of associated symptoms, tongue appearances and pulse characteristics. These limitations could be overcome by developing new strategies to evaluate the effect of Chinese medicine. The idea behind pattern-based efficacy evaluations may optimize clinical trial design by identifying the responsiveness-related Chinese medicine patterns.Methods/DesignThis is a two-stage multi-center trial of Chinese herbal medicine for the management of rheumatoid arthritis. The stage one trial is an open-label trial and aims to explore what groups of Chinese medicine information (such as symptoms) correlates with better efficacy, and the stage two trial is a randomized, controlled, double-blind, double-dummy clinical trial that incorporates the efficacy-related information identified in the stage-one trial into the inclusion criteria.DiscussionThe indication of a Chinese herbal formula is a specific Chinese medicine pattern and not a single disease and stratifying a disease into several patterns with a group of symptoms is a feasible procedure in clinical trials. This study is the first to investigate whether this approach in the design of Chinese herbal medicine trials can improve responses.Trial registrationChiCTR-TRC-10000989

A randomized, controlled, double-blinded and double-dummy trial of the effect of Tongjiang Granule (通降颗粒) on the nonerosive reflux disease of and Gan (肝)-Wei (胃) incoordination syndrome

To assess the effectiveness of tongjiang granule (TJG) on the patients with nonerosive reflux disease (NERD) of Gan-Wei incoordination syndrome, its impact on their quality of life, and its safety. A randomized, controlled, double-blinded, and double-dummy method was adopted in the trial. There were 120 NERD patients enrolled in the study and randomly divided into the experiment and control groups, each with 60 patients; drugs were distributed according to the drug number by patients' inclusion sequences. In the experiment group, patients were given TJG 10 g and mosapride citrate dummy 5 mg three times a day, and in the control group, patients were given mosapride citrate 5 mg and TJG dummy 10 g three times a day. The treatment courses of both groups were 4 weeks. Among 120 included patients, 112 were screened for full analysis set (FAS), and 105 were screened per-protocol set (PPS). The results were as follows: (1) the improvement of total scores of symptom in the experiment group (0-4 week) were 15.93±7.88 scores by FAS and 16.22 ±7.75 scores by PPS, and they were 10.43±10.16 scores and 10.79±10.27 scores in the control group, respectively. The 95% CI of net scores improvement between the two groups were 2.10-8.90 scores and 1.92-8.94 scores in FAS and PPS; it was significantly better in the experiment group than that in the control group (P<0.05). (2) The improvement of scores of major symptom in the experiment group (0-4 week) were 10.68±5.35 by FAS and 10.89±5.29 by PPS and 7.40±7.41 and 7.60±7.46 in the control group, respectively. The 95% CI of net scores improvement in the two groups were 0.85-5.71 and 0.71-5.69 in FAS and PPS separately, and the improvement in the experiment group was significantly better than that in the control group (P<0.05). (3) The total effective rates were 86.0% and 61.8% in the experiment and the control group separately, and the Ridit analysis results showed that it was better in the experiment group (P<0.05). (4) The improvement quality of life in the domain of physical functioning and general health in the experiment group was better than that in the control group (P<0.05). (5) One case of experiment group caught a cold and recovered in six days without drug suspension. No adverse event was found in the other cases. There was no meaningful safety examination indices change in pretreatment and posttreatment periods in both groups. TJG showed a definite effect on the treatment of NERD with Gan-Wei incoordination syndrome, and it could improve the quality of life of NERD patient without obvious toxic and side effects.

Zaltoprofen, a noninferior alternative to diclofenac for the treatment of primary knee osteoarthritis – a comparative evaluation of efficacy and safety in a 4-week, multicentric, randomized, double-blind, double-dummy trial

Objective: To demonstrate the clinical noninferiority of the analgesic effect of zaltoprofen (80 mg t.i.d.) compared with diclofenac (50 mg t.i.d.) in active knee osteoarthritis patients.Method: In this multicentric, double-blind, double-dummy, randomized, parallel-group, comparative study, 213 patients of either sex, aged 40 – 65 years having radiological and clinically confirmed primary knee osteoarthritis were randomized either to zaltoprofen (n = 105) or diclofenac (n = 108) and were followed-up at weeks 1, 2, 3 and 4. The treatment period was preceded by a washout period of 1 week.Results: Patients in both the zaltoprofen and diclofenac groups exhibited significant improvement (p < 0.001) in pain intensity, functional status and pain relief at each visit from baseline with no statistically significant difference between the two treatment groups. There was no statistically significant difference between the treatment groups for global assessment rating done by the patient and investigator at the end of therapy (p > 0.05) and the proportion of patients who consumed ranitidine (p = 0.135) and paracetamol (p = 0.086) tablets during the treatment period on both the treatment arms. Both the study medications were well tolerated with no incidence of serious adverse events.Conclusions: This study demonstrated that efficacy and safety of zaltoprofen is clinically noninferior to that of diclofenac.

Effect of Liposomal Lidocaine and Sucrose Alone and in Combination for Venipuncture Pain in Newborns

To determine the relative effectiveness of liposomal lidocaine, sucrose, and their combination for reducing pain in term newborns. Ours was a double-blind, randomized, controlled, double-dummy trial of 330 healthy term newborns. Before venipuncture for the newborn screening test, neonates received (1) 1 g of liposomal lidocaine cream topically, (2) 2 mL of 24% sucrose solution orally, or (3) sucrose and liposomal lidocaine. The facial grimacing score (0-100) was used to assess pain. Adverse events and lidocaine levels were used to assess safety. Infant characteristics did not differ among groups. Facial grimacing scores were lower in the sucrose group compared with those in the liposomal lidocaine group (mean difference: -27 [95% confidence interval (CI): -36 to -19; P < .001) and for the sucrose plus liposomal lidocaine group compared with those in the liposomal lidocaine group (mean difference: -23 [95% CI: -31 to -14]; P < .001). The sucrose and sucrose plus liposomal lidocaine groups did not differ (mean difference: -5 [95% CI: -13 to 4]; P = .3). Local skin reactions were not observed, and the incidence of spitting up did not differ between sucrose-exposed and non-sucrose-exposed infants (1.4% vs 2.7%, respectively; P = .22). The mean (SD) plasma lidocaine level was 44.6 (55.3) ng/mL. Sucrose was more effective than liposomal lidocaine for reducing pain during venipuncture in newborns. The addition of liposomal lidocaine to sucrose did not confer any additional benefit to sucrose alone. There was no evidence of harm from liposomal lidocaine or sucrose.