Double blind,randomised, placebo controlled study of four weeks of lansoprazole for the treatment of functional dyspepsia in Chinese patients

BACKGROUND: The use of proton pump inhibitors for the treatment of functional dyspepsia is controversial and the role of Helicobacter pylori infection in functional dyspepsia is uncertain. AIM: To evaluate the efficacy of different doses of lansoprazole for the treatment of functional dyspepsia in Chinese patients. METHOD: Patients with a clinical diagnosis of functional dyspepsia according to the Rome II criteria and normal upper gastrointestinal endoscopy were recruited and randomised to receive: (1) lansoprazole 30 mg, (2) lansoprazole 15 mg, or (3) placebo, all given daily for four weeks. Dyspepsia symptom scores and quality of life (SF-36 score) were evaluated before and four weeks after treatment. RESULTS: A total of 453 patients were randomised. There was no difference in the proportion of patients with complete symptom relief in the lansoprazole 30 mg (23%) and lansoprazole 15 mg (23%) groups compared with the placebo group (30%). The proportion of H pylori positive patients with a complete response was similar with lansoprazole 30 mg (34%) and lansoprazole 15 mg (20%) versus placebo (22%). All symptom subgroups (ulcer-like, dysmotility-like, reflux-like, and unspecified dyspepsia) had similar proportions of patients with complete symptom relief after treatment. CONCLUSION: Proton pump inhibitor treatment is not superior to placebo for the management of functional dyspepsia in Chinese patients.     

A phase II,randomized, double‐blind,placebo‐controlled,dose‐ranging study of belimumab in patients with active systemic lupus erythematosus

Objective

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).

Methods

Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52‐week study. Coprimary end points were the percent change in the SELENA–SLEDAI score at week 24 and the time to first SLE flare.

Results

Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA–SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24–52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer ≥1:80 and/or anti–double‐stranded DNA [anti‐dsDNA] ≥30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA–SLEDAI score (?28.8% versus ?14.2%; P = 0.0435), physician's global assessment (?32.7% versus ?10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63–71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti‐dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.

Conclusion

Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

     

Dutogliptin,a selective DPP4 inhibitor,improves glycaemic control in patients with type 2 diabetes: a 12‐week,double‐blind,randomized, placebo‐controlled,multicentre trial

Aim: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. Methods: This was a 12‐week, multicentre, randomized, double‐blind, placebo‐controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2‐week single‐blind placebo run‐in, patients aged 18–75 years with a body mass index of 25–48 kg/m² and baseline HbA1c of 7.3–11.0% were randomized 2:2:1 to receive once‐daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. Results: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by ?0.52% (p < 0.001) and ?0.35% (p = 0.006), respectively (placebo‐corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of ?0.82, ?0.64 and ?0.3%, respectively. The proportion of patients achieving an HbA1c < 7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo‐corrected difference was ?1.00 mmol/l (p < 0.001) for the 400 mg group and ?0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC _0–2h in both the 400 and 200 mg groups (placebo corrected values ?2.58 mmol/l/h, p < 0.001 and ?1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin‐treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12‐week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. Conclusions: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of < 7% than the 200 mg dose.     

Eradication ofHelicobacter pylori and long-term outcome of functional dyspepsia

The aim of this study was to assess the effect of colloidal bismuth subcitrate (CBS) and metronidazole on Helicobacter pylori eradication and on the course of symptoms due to functional dyspepsia. Forty-one patients with functional dyspepsia were entered into the study and randomized to treatment with CBS (120 mg four times a day) for four weeks combined with metronidazole (250 mg four times a day) for one week (group A,N=21) or matching placebo (group B,N=20). The severity of gastritis and of bacterial colonization and the symptom score was assessed by endoscopy and clinical evaluation at baseline and after four, eight, and 24 weeks from the start of the treatment. With intent-to-treat analysis eradication was achieved in 16/25 (64%) patients in group A and in 6/24 (25%) in group B. At eight and 24 weeks the gastritis score was significantly lower only in those patients with eradication. No change was seen in patients in whom the bacteria was not eradicated. The symptom score at eight weeks was considerably lower both in patients with eradication and in those with infection. However, at 24 weeks a gradual decrease in the symptom score in patients with eradication and a worsening of symptoms in controls was observed. No differences were observed between patients with ulcerlike and those with dysmotility-like dyspepsia. The study confirms the need for a long observation period after antibacterial treatment in patients with functional dyspepsia and suggests thatHelicobacter pylori-eradicating treatment improves the course of this functional syndrome.     

Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA).

Methods

This phase II, multicenter, randomized, double‐blind, placebo‐controlled study included the following: a 12‐week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12‐week treatment‐extension phase, with patients in the placebo group re‐randomized to receive apremilast; and a 4‐week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms.

Results

Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment‐extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re‐randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment‐extension phase (68.3%) reported ≥1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported.

Conclusion

Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.

     

Evaluation of the efficacy and safety of terguride in patients with fibromyalgia syndrome: Results of a twelve‐week,multicenter, randomized,double‐blind,placebo‐controlled,parallel‐group study

Objective

To assess the efficacy and safety of terguride, a partial dopamine agonist, in patients with fibromyalgia syndrome (FMS).

Methods

In a 12‐week, multicenter, double‐blind, placebo‐controlled, parallel‐group study, 99 patients were randomized at a ratio of 2 to 1 to receive terguride or placebo. Over 21 days, the dosage was titrated to a maximum daily dose of 3 mg of terguride or placebo, and this fixed dosage was continued over 9 weeks. The primary efficacy variable was the intensity of pain (100‐mm visual analog scale). Secondary efficacy variables included the Fibromyalgia Impact Questionnaire (FIQ) score, the tender point score (TPS), and the Hamilton Depression Scale (HDS) score. During the study, patients were evaluated for the presence of cervical spine stenosis by magnetic resonance imaging (MRI).

Results

No significant differences in the change in pain intensity, FIQ score, TPS, or HDS score between baseline and 12 weeks were observed in the terguride group as compared with the placebo group. Cervical spine stenosis was detected in 22% of the patients. Only patients with cervical spine stenosis responded to terguride treatment. FIQ scores improved significantly (per‐protocol analysis), and pain intensity, the TPS score, and the HDS score showed a trend toward improvement in the terguride group as compared with the placebo group. Terguride treatment was safe. Only those adverse events already known to be side effects of terguride were observed. Premature termination of the study in patients receiving terguride (26%) occurred predominantly during up‐titration and in the absence of comedication for treatment of nausea.

Conclusion

Terguride treatment did not improve pain, the FIQ score, the TPS, or the HDS score in the total study population. However, a subgroup of patients with cervical spine stenosis seemed to benefit from terguride treatment.

     

复方消化酶治疗消化不良患者的疗效和安全性随机双盲安慰剂对照多中心临床试验

目的 评估复方消化酶(商品名:美尼)治疗消化不良的疗效和安全性.方法 采用随机双盲、安慰剂平行对照的多中心研究.应用视觉模拟评分法(visual analogue scale,VAS),食欲不振、饱胀、腹部不适和腹胀症状总积分≥20分的消化不良患者240例,随机均分为安慰剂组和治疗组,分别服用安慰剂和复方消化酶2粒/次,3次/d,疗程为2周;评价两组在治疗1、2周和停药后1周消化不良症状的缓解程度和不良反应的发生.结果 216例患者完成本研究,其中治疗组105例,安慰剂组111例.治疗组在治疗1、2周及停药1周消化不良总症状积分下降程度明显优于安慰剂组(P＜0.01);治疗组在治疗1、2周和停药后1周总有效率分别为64.76%、77.05%和66.99%,明显高于安慰剂组的27.93%、37.84%和29.36%(P＜0.05).两组在治疗过程中及停药后均未出现严重不良反应.结论 复方消化酶治疗消化不良具有良好的疗效及安全性.     

Therapeutic benefit of blocking interleukin‐6 activity with an anti–interleukin‐6 receptor monoclonal antibody in rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled,dose‐escalation trial

Objective

To investigate the safety and efficacy of MRA, a recombinant human anti–interleukin‐6 (anti–IL‐6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL‐6, in patients with established rheumatoid arthritis (RA).

Methods

A randomized, double‐blind, placebo‐controlled, dose‐escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment.

Results

Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1‐ and 1‐mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C‐reactive protein values fell significantly in the 5‐ and 10‐mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1‐, 1‐, 5‐, and 10‐mg/kg MRA cohorts, respectively) required corticosteroid or disease‐modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1‐, 1‐, and 10‐mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug.

Conclusion

This is the first randomized controlled trial showing that inhibition of IL‐6 significantly improved the signs and symptoms of RA and normalized the acute‐phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.

     

Sifalimumab,a Human Anti–Interferon‐α Monoclonal Antibody,in Systemic Lupus Erythematosus: A Phase I Randomized,Controlled, Dose‐Escalation Study

Objective

To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate‐to‐severe systemic lupus erythematosus (SLE).

Methods

In this multicenter, double‐blind, placebo‐controlled, sequential dose‐escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment‐emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.

Results

Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate‐to‐severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment‐emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose‐proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.

Conclusion

The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

     

Radiographic,clinical, and functional outcomes of treatment with adalimumab (a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized,placebo‐controlled, 52‐week trial

Objective

Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti–TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX).

Methods

In this multicenter, 52‐week, double‐blind, placebo‐controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]).

Results

At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean ± SD change 0.1 ± 4.8) or 20 mg weekly (0.8 ± 4.9) as compared with that in the placebo group (2.7 ± 6.8) (P ≤ 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P ≤ 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P ≤ 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score −0.59 and −0.61, respectively, versus −0.25; P ≤ 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab‐treated patients and in 30.0% of placebo‐treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P ≤ 0.02), and was highest in the patients receiving 40 mg every other week.

Conclusion

In this 52‐week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.

     

A randomized,double‐blind,placebo‐controlled trial of pramipexole,a dopamine agonist,in patients with fibromyalgia receiving concomitant medications

Objective

To assess the efficacy and safety of pramipexole, a dopamine 3 receptor agonist, in patients with fibromyalgia.

Methods

In this 14‐week, single‐center, double‐blind, placebo‐controlled, parallel‐group, escalating‐dose trial, 60 patients with fibromyalgia were randomized 2:1 (pramipexole:placebo) to receive 4.5 mg of pramipexole or placebo orally every evening. The primary outcome was improvement in the pain score (10‐cm visual analog scale [VAS]) at 14 weeks. Secondary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ), the Multidimensional Health Assessment Questionnaire (MDHAQ), the pain improvement scale, the tender point score, the 17‐question Hamilton Depression Inventory (HAM‐d), and the Beck Anxiety Index (BAI). Patients with comorbidities and disability were not excluded. Stable dosages of concomitant medications, including analgesics, were allowed.

Results

Compared with the placebo group, patients receiving pramipexole experienced gradual and more significant improvement in measures of pain, fatigue, function, and global status. At 14 weeks, the VAS pain score decreased 36% in the pramipexole arm and 9% in the placebo arm (treatment difference –1.77 cm). Forty‐two percent of patients receiving pramipexole and 14% of those receiving placebo achieved ≥50% decrease in pain. Secondary outcomes favoring pramipexole over placebo included the total FIQ score (treatment difference –9.57) and the percentages of improvement in function (22% versus 0%), fatigue (29% versus 7%), and global (38% versus 3%) scores on the MDHAQ. Compared with baseline, some outcomes showed a better trend for pramipexole treatment than for placebo, but failed to reach statistical significance, including improvement in the tender point score (51% versus 36%) and decreases in the MDHAQ psychiatric score (37% versus 28%), the BAI score (39% versus 27%), and the HAM‐d score (29% versus 9%). No end points showed a better trend for the placebo arm. The most common adverse events associated with pramipexole were transient anxiety and weight loss. No patient withdrew from the study because of inefficacy or an adverse event related to pramipexole.

Conclusion

In a subset of patients with fibromyalgia, ∼50% of whom required narcotic analgesia and/or were disabled, treatment with pramipexole improved scores on assessments of pain, fatigue, function, and global status, and was safe and well‐tolerated.

     

Golimumab in psoriatic arthritis: One‐year clinical efficacy,radiographic, and safety results from a phase III,randomized, placebo‐controlled trial

Objective

Golimumab, administered subcutaneously every 4 weeks, has been shown to be effective in reducing the signs and symptoms of active psoriatic arthritis (PsA) through week 24 of the GO‐REVEAL study. Herein we report 1‐year clinical, radiographic, and safety findings.

Methods

Adult patients with active PsA (≥3 swollen and ≥3 tender joints) were randomly assigned to receive subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks through week 20. At week 16, patients with <10% improvement from baseline in swollen and tender joint counts entered a blinded early escape phase, with placebo crossover to golimumab 50 mg, golimumab 50 mg increased to 100 mg, and golimumab 100 mg continued at 100 mg. Patients receiving placebo who did not enter the early escape phase crossed over to golimumab 50 mg at week 24. Findings through 1 year are reported, including the second of 2 coprimary end points (i.e., change from baseline to week 24 in PsA‐modified Sharp/van der Heijde score [SHS]).

Results

A total of 405 patients were randomized: 113 to placebo and 146 each to the golimumab 50 mg and 100 mg groups. Mean changes in PsA‐modified SHS from baseline to week 24 for the combined golimumab 50 mg and 100 mg group (−0.09) and the golimumab 50 mg group (−0.16) were significantly different versus placebo (0.27) (P = 0.015 and P = 0.011, respectively). Radiographic benefit was maintained through week 52 with golimumab. Clinical efficacy, including improvement in joint and skin responses and physical function, was maintained through 1 year. The frequency/types of adverse events were similar to those reported through week 24.

Conclusion

Treatment of PsA with golimumab inhibited structural damage progression and demonstrated continued clinical efficacy and safety through 1 year.

     

Efficacy and safety of teneligliptin,a novel dipeptidyl peptidase‐4 inhibitor,in Korean patients with type 2 diabetes mellitus: a 24‐week multicentre,randomized, double‐blind,placebo‐controlled phase III trial

We assessed the 24‐week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase‐4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were ?0.94% [least‐squares (LS) mean ?1.22, ?0.65] and ?1.21 mmol/l (?1.72, ?0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo‐controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM.     

Gabapentin in the treatment of fibromyalgia: A randomized,double‐blind,placebo‐controlled,multicenter trial

Objective

To assess the efficacy and safety of gabapentin in patients with fibromyalgia.

Methods

A 12‐week, randomized, double‐blind study was designed to compare gabapentin (1,200–2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0–10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of ≥30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent‐to‐treat sample, with treatment‐by‐time interaction as the measure of effect.

Results

Gabapentin‐treated patients displayed a significantly greater improvement in the BPI average pain severity score (P = 0.015; estimated difference between groups at week 12 = −0.92 [95% confidence interval −1.75, −0.71]). A significantly greater proportion of gabapentin‐treated patients compared with placebo‐treated patients achieved response at end point (51% versus 31%; P = 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.

Conclusion

Gabapentin (1,200–2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.

     

复方碳酸氢钠栓治疗功能性便秘的多中心、随机、双盲、安慰剂对照临床试验

背景：功能性便秘是一种常见慢性肠道功能性疾病，目前其治疗药物虽较多，但疗效不尽如人意。目的：观察复方碳酸氢钠栓治疗功能性便秘的临床疗效和安全性。方法：2006年5月-2007年5月由6家医院进行多中心、随机、双盲、安慰剂对照临床试验。1周筛选期后，218例功能性便秘患者随机分为试验组和对照组，每组109例，分别给予复方碳酸氢钠栓和安慰剂纳肛，1粒／d，连续7d。治疗第1d，用药1次后若无排便，可重复用药1次。治疗第2d起每日用药1次。受试者每日记录排便次数、大便性状以及排便费力、排便不尽感、服用缓泻剂天数和药物用量。结果：治疗1周后，与治疗前和对照组相比，试验组周排便次数、周大便性状、周排便不尽感天数均显著改善（P〈0．05），但两组周排便费力天数、周服用缓泻剂天数和周药物用量相比差异均无统计学意义。两组均未出现严重不良事件。结论：复方碳酸氢钠栓治疗功能性便秘有效而安全。     

Esomeprazole 40 mg once a day in patients with functional dyspepsia: the randomized, placebo-controlled "ENTER" trial

OBJECTIVE: The etiologies of functional dyspepsia (FD) are unclear, but in some studies, treatment with a proton pump inhibitor has been beneficial. The objective of this study was to evaluate the efficacy of esomeprazole 40 mg once a day compared to placebo in achieving symptom relief in primary care patients with FD. METHODS: This was a randomized, placebo-controlled trial in adult FD patients, who had at least moderate severity of symptoms, defined as a score of > or =4 on a 7-point Global Overall Symptom (GOS) scale. Patients were excluded if they had predominant symptoms of heartburn or regurgitation; after a normal baseline endoscopy, patients were randomized to esomeprazole 40 mg once daily or placebo for 8 wk. The primary outcome measure was symptom relief (GOS < or =2) at 8 wk. RESULTS: Of the 502 enrolled patients, 224 were randomized. The main reasons for exclusion were abnormal endoscopic findings, especially esophagitis. A significantly greater proportion of patients in the esomeprazole group achieved symptom relief at 4 but not at 8 wk compared to placebo: 4 wk esomeprazole 50.5% versus placebo 32.2%, p= 0.009; 8 wk esomeprazole 55.1% versus placebo 46.1%, p= 0.16. A similar relationship at 4 and 8 wk was seen for symptom resolution (GOS = 1) and improvement (DeltaGOS > or =2). CONCLUSION: For the primary outcome measure of symptom relief at 8 wk, there was no statistically significant difference between esomeprazole 40 mg once a day and placebo. However, at 4 wk, esomeprazole was significantly more effective than placebo for symptom relief. The difference in therapeutic gain between 4 and 8 wk was largely due to a higher placebo response rate at 8 wk.     

The once‐daily human glucagon‐like peptide‐1 analog,liraglutide, improves β‐cell function in Japanese patients with type 2 diabetes

Aims/Introduction: β‐cell function was evaluated by homeostasis model assessment of β‐cell function (HOMA‐B) index, proinsulin:insulin and proinsulin:C‐peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide. Materials and Methods: Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA_1c] 8.61–9.32%; body mass index [BMI] 24.4–25.3 kg/m²) were analyzed. In two 24‐week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B). Results: Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide‐treated groups in trials A and B, area under the curve (AUC) _{insulin 0–3 h} was improved (P < 0.001 for all) and the AUC_{insulin 0–3 h}:AUC_{glucose 0–3 h} ratio was increased (estimated treatment difference [liraglutide–comparator] 0.058 [0.036, 0.079]). HOMA‐B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups. Conclusions: In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved β‐cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI‐060328 and trial B: no. NCT00395746/JapicCTI‐060324). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00193.x, 2012)     

LY2439821, a humanized anti–interleukin‐17 monoclonal antibody,in the treatment of patients with rheumatoid arthritis: A phase I randomized,double‐blind,placebo‐controlled,proof‐of‐concept study

Objective

We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin‐17 (anti–IL‐17) monoclonal antibody, in a first in‐human trial in rheumatoid arthritis (RA) patients taking oral disease‐modifying antirheumatic drugs (DMARDs).

Methods

This randomized, double‐blind, placebo‐controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.

Results

Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all‐LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821‐treated patients than in placebo‐treated patients at multiple time points. There was no apparent dose‐response relationship in treatment‐emergent adverse events.

Conclusion

LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL‐17 as a potential novel goal for the treatment of RA.

     

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a forty‐eight–week randomized,double‐blind,placebo‐controlled,parallel‐group phase III trial

Objective

To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX.

Methods

STAGE was a phase III randomized, double‐blind, parallel‐group international study to evaluate the safety and efficacy of ocrelizumab compared with placebo in patients with active RA continuing MTX treatment. Patients receiving stable doses of MTX were randomized to receive 2 infusions of placebo (n = 320), ocrelizumab 200 mg (n = 343), or ocrelizumab 500 mg (n = 343) on days 1 and 15 as well as weeks 24 and 26. Coprimary end points were the proportion of patients with an American College of Rheumatology 20% improvement criteria (ACR20) response at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses.

Results

The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks (P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3‐fold as compared with placebo and showed a statistically significant (P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200‐mg and 500‐mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient‐years) and ocrelizumab 200 mg (3.54 per 100 patient‐years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient‐years).

Conclusion

With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression of joint damage. A higher rate of serious infections was observed with 500 mg of ocrelizumab as compared with ocrelizumab 200 mg or placebo.

     

Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS).

Methods

This was a randomized, multicenter, double‐blind, placebo‐controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24‐week double‐blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index.

Results

The spine SPARCC score in placebo‐treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab‐treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo‐treated patients and by 52.9% in adalimumab‐treated patients (P = 0.017). The response in adalimumab‐treated patients was maintained at week 52. Placebo‐treated patients were switched to open‐label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab‐treated patients, a reduced C‐reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018).

Conclusion

Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.