Antrafenine, naproxen and placebo in osteoarthritis: a comparative study

Antrafenine is a new non-narcotic analgesic. In a double-blind, cross-over study the efficacy of antrafenine at doses of 450 mg/day and 900 mg/day was compared to naproxen 750 mg/day and placebo in patients with osteoarthritis. Each drug treatment was given for two weeks, the total duration of the study being eight consecutive weeks. Antrafenine, at either dose, was effective in relieving pain associated with osteoarthritis; the efficacy was comparable to naproxen. There was no definite indication that 900 mg/day was more effective than 450 mg/day. Antrafenine, at both dosage levels, was well tolerated. Any noted side-effects were mild. There was a total of 12 side-effects in nine patients with the high dose, five side-effects in five patients with the low dose, compared with 11 side-effects in nine patients with naproxen and 10 side-effects in seven patients with placebo.     

Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects

OBJECTIVE: The objective of this endoscopic study was to compare the effects on the gastroduodenal mucosa of healthy volunteers of different doses and dosing regimens of AZD3582, a cyclooxygenase-inhibiting nitric oxide donator (CINOD), with equimolar doses of naproxen. MATERIAL AND METHODS: Healthy volunteers were enrolled in a single-centre, randomized, double-blind, crossover trial consisting of two 12-day treatment periods and employing six sequences. The groups were: AZD3582 750 mg daily versus 375 mg twice daily (n=25), AZD3582 375 mg twice daily versus 750 mg twice daily (n=25) and naproxen 250 mg twice daily versus 500 mg twice daily (n=25). RESULTS: Gastroduodenal tract damage was similar with AZD3582 375 mg twice daily and 750 mg twice daily (mean number of erosions and ulcers+/-SD: 2.88+/-3.95 versus 3.08+/-2.80, respectively; p=0.824; 1 ulcer counted as 10 erosions). There was an indication of decreased gastroduodenal toxicity with AZD3582 750 mg daily compared with 375 mg twice daily (0.92+/-2.08 versus 2.71+/-4.75, respectively; p=0.068). Gastroduodenal toxicity was significantly lower with AZD3582 375 mg twice daily than with naproxen 250 mg twice daily (2.88+/-3.95 versus 6.16+/-9.36; p<0.05), and with AZD3582 750 mg twice daily versus naproxen 500 mg twice daily (3.08+/-2.80 versus 6.68+/-6.97; p<0.05). Equimolar twice-daily doses of AZD3582 and naproxen resulted in similar naproxen plasma levels and serum thromboxane B(2) inhibition. CONCLUSIONS: AZD3582 has an improved gastroduodenal safety profile compared with equimolar doses of naproxen. The gastroduodenal effects of AZD3582 375 mg and AZD3582 750 mg twice daily are similar. A once-daily regimen of AZD3582 might be less gastrotoxic than a twice-daily regimen.     

Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial

OBJECTIVE: To compare epicutaneous ketoprofen in Transfersome (ultra-deformable vesicles, IDEA-033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis. METHODS: This was a multicentre, randomised, double-blind, controlled trial; 397 patients with knee osteoarthritis participated and 324 completed the trial. They were randomly assigned 110 mg epicutaneous ketoprofen in 4.8 g Transfersome plus oral placebo (n = 138), 100 mg oral celecoxib plus placebo gel (n = 132), or both placebo formulations (n = 127) twice daily for 6 weeks. Primary efficacy outcome measures were the changes from baseline to end of the study on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale, physical function subscale and patient global assessment (PGA) of response. RESULTS: The mean WOMAC pain subscale scores in the intent to treat population were reduced by 18.2 (95% confidence interval -22.1 to -14.3), 20.3 (-24.3 to -16.2) and 9.9 (-13.9 to -5.8) in the IDEA-033, celecoxib and placebo groups, respectively, and the physical function subscale score by 14.6 (-18.1 to -11.0), 16.6 (-20.2 to -13.0) and 10.2 (-13.8 to -6.6), respectively. The mean PGA of response scores were 1.8 (1.6 to 2.1), 1.7 (1.5 to 1.9) and 1.3 (1.1 to 1.5), respectively. The differences in change between IDEA-033 and placebo were statistically significant for pain subscale (p<0.01) and PGA of response (p<0.01). Gastrointestinal adverse events for IDEA-033 were similar to placebo. CONCLUSION: IDEA-033 is superior to placebo and comparable with celecoxib in relieving pain associated with an acute flare of knee osteoarthritis.     

Comparison of timegadine and naproxen in rheumatoid arthritis. A placebo controlled trial

A double blind, cross-over design was used to compare the acute effects of timegadine, naproxen and placebo in rheumatoid arthritis. Timegadine appeared to be more effective than naproxen in those variables related to disease activity although there were no statistically significant differences (apart from morning stiffness) where variables were examined individually. There was a tendency to a rise in alkaline phosphatase, and possibly gamma glutamyl transpeptidase, during the 2-week timegadine treatment period. No other biochemical or haematological abnormality was observed.     

Efficacy of physiotherapy management of knee joint osteoarthritis: a randomised, double blind, placebo controlled trial

OBJECTIVE: To determine whether a multimodal physiotherapy programme including taping, exercises, and massage is effective for knee osteoarthritis, and if benefits can be maintained with self management. METHODS: Randomised, double blind, placebo controlled trial; 140 community volunteers with knee osteoarthritis participated and 119 completed the trial. Physiotherapy and placebo interventions were applied by 10 physiotherapists in private practices for 12 weeks. Physiotherapy included exercise, massage, taping, and mobilisation, followed by 12 weeks of self management. Placebo was sham ultrasound and light application of a non-therapeutic gel, followed by no treatment. Primary outcomes were pain measured by visual analogue scale and patient global change. Secondary measures included WOMAC, knee pain scale, SF-36, assessment of quality of life index, quadriceps strength, and balance test. RESULTS: Using an intention to treat analysis, physiotherapy and placebo groups showed similar pain reductions at 12 weeks: -2.2 cm (95% CI, -2.6 to -1.7) and -2.0 cm (-2.5 to -1.5), respectively. At 24 weeks, pain remained reduced from baseline in both groups: -2.1 (-2.6 to -1.6) and -1.6 (-2.2 to -1.0), respectively. Global improvement was reported by 70% of physiotherapy participants (51/73) at 12 weeks and by 59% (43/73) at 24 weeks. Similarly, global improvement was reported by 72% of placebo participants (48/67) at 12 weeks and by 49% (33/67) at 24 weeks (all p>0.05). CONCLUSIONS: The physiotherapy programme tested in this trial was no more effective than regular contact with a therapist at reducing pain and disability.     

Evaluation of the efficacy and safety of etoricoxib compared with naproxen in two, 138-week randomised studies of patients with osteoarthritis

OBJECTIVES: To assess the efficacy and safety of etoricoxib 60 mg once daily and naproxen 500 mg twice daily over a 138-week treatment period in patients with osteoarthritis (OA). METHODS: Two 1-year randomised, double blind, parallel group two-part base studies (part I 12 weeks; part II 40 weeks), followed by an 86-week extension, in patients with OA (hip or knee) were conducted at 80 clinical centres (19 countries). The studies had identical designs. Patients taking placebo in part I received etoricoxib or naproxen (1:1 ratio) in part II and the extension; patients taking etoricoxib or naproxen in part I continued to receive the same treatment throughout the entire length of the studies. Co-primary efficacy end points were patient global assessment of disease status, and WOMAC questionnaire pain subscale and physical function subscale (100 mm VAS). Efficacy over 138 weeks was assessed by graphical analysis. Safety was assessed by observation of adverse experiences and laboratory and physical evaluations. RESULTS: 997 patients entered (615 completed) the base studies. Of these patients, 463 patients entered the extensions. A total of 161 and 152 patients in the etoricoxib and naproxen groups, respectively, completed 138 treatment weeks. Etoricoxib and naproxen showed similar efficacy throughout the 138 weeks of treatment. For etoricoxib and naproxen, respectively, WOMAC pain assessments were 67 and 67 mm (baseline); 28 and 29 mm (1 year), and 34 and 33 mm (138 weeks). Results for the other efficacy end points were similar to those seen with the WOMAC pain assessments. Both etoricoxib and naproxen were generally well tolerated. CONCLUSION: Both etoricoxib and naproxen demonstrated long-term clinical efficacy for the treatment of OA. Etoricoxib and naproxen were generally well tolerated.     

A randomized,controlled trial of methotrexate versus placebo in early diffuse scleroderma

Objective

Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc.

Methods

Seventy‐one patients with diffuse SSc of <3 years' duration were enrolled in a multicenter, randomized, placebo‐controlled, double‐blind trial. Thirty‐five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment.

Results

At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLCO ), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. At study completion, results slightly favored the MTX group (mean ± SEM modified Rodnan skin score 21.4 ± 2.8 in the MTX group versus 26.3 ± 2.1 in the placebo group [P < 0.17]; UCLA skin score 8.8 ± 1.2 in the MTX group versus 11.0 ± 0.9 in the placebo group [P < 0.15]; DLCO in the MTX group 75.7 ± 4.6 versus 61.8 ± 3.4 in the placebo group [P < 0.2]). In addition, physician global assessment results favored MTX (P < 0.035), whereas patient global assessment did not differ significantly between groups. When between‐group differences for changes in scores from baseline to 12 months were examined using intent‐to‐treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score −4.3 in the MTX group versus 1.8 in the placebo group [P < 0.009]; UCLA score −1.2 in the MTX group versus 1.2 in the placebo group [P < 0.02]), but differences in the degree of change in the DLCO and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use. Dropout rates were similar in the 2 groups.

Conclusion

Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between‐group differences were small and the power to rule out false‐negative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc.

     

A double blind randomised placebo controlled trial of hexopal in primary Raynaud's disease

Summary The peripheral vasospastic symptoms associated with Raynaud's disease continue to be an unsolved clinical problem. Hexopal (Hexanicotinate inositol) has shown promise in uncontrolled studies and its use in patients with Raynaud's disease may reduce such vasospasm. This study examines the effects of 4 g/day of Hexopal or placebo, during cold weather, in 23 patients with primary Raynaud's disease. The Hexopal group felt subjectively better and had demonstrably shorter and fewer attacks of vasospasm during the trial period. Serum biochemistry and rheology was not significantly different between the two groups. Although the mechanism of action remains unclear Hexopal is safe and is effective in reducing the vasospasm of primary Raynaud's disease during the winter months.

     

A randomised placebo controlled trial of pegylated interferon alpha in active ulcerative colitis

BACKGROUND: Pilot studies of interferon alpha (IFN-alpha) suggest a high remission rate in the treatment of active ulcerative colitis. We evaluated the safety of pegylated interferon alpha (PegIFN) and its role in induction of remission in patients with active ulcerative colitis, in a multicentre placebo controlled trial. METHODS: Sixty patients with a clinical activity score (CAI) of >6 were randomised to receive placebo (n=20), PegIFN 0.5 microg/kg (n=19), or PegIFN 1.0 microg/kg body weight (n=21) once weekly (PegIntron; Schering-Plough, USA) over 12 weeks. Patients receiving 5-aminosalicylates, steroids, and/or azathioprine in stable dosages were included. RESULTS: Serious adverse events were seen in none of the placebo patients, in 3/19 patients in the PegIFN 0.5 microg/kg group (hospitalisation due to disease flare up n=3), and in 3/21 in the PegIFN 1.0 microg/kg group (hospitalisation due to disease flare up n=1; thrombosis n=1; grand mal seizure n=1). Otherwise, we observed only minor IFN-alpha side effects. Clinical remission rates at week 12 (CAI < or =4) were 7/20 (35%) in the placebo, 9/19 (47%) in the PegIFN 0.5 microg/kg group, and 7/21 (33%) in the PegIFN 1.0 microg/kg group (NS). Early withdrawal from the study was observed in 11/20 placebo patients, in 6/19 in the PegIFN 0.5 microg/kg group, and in 10/21 in the PegIFN 1.0 microg/kg group, mainly due to lack of efficacy. The higher PegIFN dose was associated with a significant decrease in levels of C reactive protein (p=0.003, day 0 v 85). CONCLUSIONS: PegIFN is safe but not effective, at the dosages used, in patients with ulcerative colitis.     

A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis

OBJECTIVES: To compare budesonide, a locally acting glucocorticoid with minimal systemic exposure, with conventional glucocorticoid treatment and placebo in rheumatoid arthritis. METHODS: A double blind, randomised, controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis, comparing budesonide 3 mg daily, budesonide 9 mg daily, prednisolone 7.5 mg daily, and placebo. Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment. RESULTS: There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo (28% for tender and 34% for swollen joint counts, p<0.05). Prednisolone 7.5 mg gave similar results, while budesonide 3 mg was less effective. ACR20 response criteria were met by 25% of patients on placebo, 22% on budesonide 3 mg, 42% on budesonide 9 mg, and 56% on prednisolone 7.5 mg. A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks. There was no evidence that budesonide provided a different pattern of symptom control from prednisolone, or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment. Adverse effects attributable to glucocorticoids were equally common in all groups. CONCLUSIONS: The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment, are maintained for three months, and are not associated with any rebound in symptoms after stopping treatment.     

Ketanserin versus placebo in carcinoid syndrome. A clinical controlled trial

Seven patients, four women and three men, with a median age of 64 years (range, 53-74 years) were randomized to treatment with either ketanserin, 40-160 mg daily, or placebo. The study included 13 treatment periods with ketanserin and 13 with placebo. All patients had typical symptoms, with flushing as their main complaint. The diagnosis had been verified histologically. All had elevated excretion of 5-hydroxy-3-indoleacetic acid in urine. During the trial ketanserin reduced the number of flushing attacks in five patients (p less than 0.05). Diarrhoea was reduced in two patients. No side effects were observed. Ketanserin seems valuable for the symptomatic relief in the carcinoid syndrome.     

A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma.

OBJECTIVE: Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc. METHODS: Seventy-one patients with diffuse SSc of <3 years' duration were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial. Thirty-five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment. RESULTS: At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLco), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. At study completion, results slightly favored the MTX group (mean +/- SEM modified Rodnan skin score 21.4+/-2.8 in the MTX group versus 26.3+/-2.1 in the placebo group [P < 0.17]; UCLA skin score 8.8+/-1.2 in the MTX group versus 11.0+/-0.9 in the placebo group [P < 0.15]; DLco in the MTX group 75.7+/-4.6 versus 61.8+/-3.4 in the placebo group [P < 0.2]). In addition, physician global assessment results favored MTX (P < 0.035), whereas patient global assessment did not differ significantly between groups. When between-group differences for changes in scores from baseline to 12 months were examined using intent-to-treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score -4.3 in the MTX group versus 1.8 in the placebo group [P < 0.009]; UCLA score -1.2 in the MTX group versus 1.2 in the placebo group [P < 0.02]), but differences in the degree of change in the DLco and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use. Dropout rates were similar in the 2 groups. CONCLUSION: Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between-group differences were small and the power to rule out false-negative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc.     

A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis

Summary A multicentre, double-blind study of unprecedented size was conducted to compare the safety and efficacy of piroxicam and naproxen in the treatment of osteoarthritis. The study comprised 2,035 patients and a treatment period of 12 weeks. The dosage was 20 mg piroxicam and 750 mg naproxen daily with the option to reduce to 10 and 500 mg, respectively, at week 4 or 8. No major difference between the drugs was observed with regard to overall incidence of adverse events. The frequency of serious adverse events was about 1% for both drugs. A statistically significant decline of adverse events with age was found in both sexes. Piroxicam was significantly superior to naproxen for pain at rest and pain on movement at 12 weeks and degree of restriction in daily activity at 4 weeks. A significantly increasing beneficial effect was observed with both drugs between 4 and 12 weeks of treatment. The comparable safety observed for the two drugs is in contrast to perceptions based on spontaneous reports to official monitoring systems.     

A comparative trial of benoxaprofen and naproxen.

A double-blind within-patient trial in rheumatoid arthritis comparing the new anti-inflammatory drug benoxaprofen with naproxen is reported. Patients received naproxen 250 mg b.d. for two weeks and benoxaprofen 200 mg b.d. for three weeks. Both drugs demonstrated efficacy. There was no statistically significant difference between them, except for grip strength which favoured naproxen. Side-effects were mild, infrequent and similar for both drugs. Evidence is presented which confirms the long duration of action of benoxaprofen, a fact which may be of clinical significance.     

A prospective randomised controlled clinical trial comparing the efficacy of different molecular weight hyaluronan solutions in the treatment of knee osteoarthritis

Viscosupplementation consists of injecting exagenous hyaluronan (HA) into the synovial joints to restore the normal rheological environment which deteriorates severely in osteoarthritic (OA) joints. Efficacy might be related to the rheological properties and molecular weight (MW) of the hyaluronan preparations. This prospective, controlled, double-blind, randomised clinical trial was aimed at comparing the elastoviscous properties of a high molecular weight viscosupplement, hylan G-F 20, with that of a lower molecular weight hyaluronan product in order to determine the relationship of elastoviscosity to efficacy, alongside placebo, in the treatment of patients with knee OA. The results were analysed as a completers analysis with 59 patients. Primary outcome measures included the Western Ontario and Mc Master Universities Osteoarthritis Index (WOMAC) for pain, stiffness and function scores, and patient and physician global assessments (0–100 scale). For patient (PGA) and physician global assessments (PhGA), the 0–100 scale was used, with 100 being the worst. Follow-up assessments were made at intervals of 1, 3 and 6 months after the first injection. Local adverse events, such as transient pain at the injection site or warm knee lasting for one night, were recorded in two patients (3%). In all groups, the WOMAC pain score exhibited a significant difference from the baseline value; neither treatment group was significantly different from the placebo group, but total pain score was significantly better than baseline for both of the HA groups at the end of 6 months (p < 0.05). Improvement in WOMAC physical function score favoured both sodium hyaluronate and hylan G-F 20 after the first month, and remained significant until the end of 6 months (p < 0.01). In the placebo group, the physical function scores became worse after the end of the 1st month; the scores at the end of 6 months were no different from those at the beginning. The WOMAC stiffness scores of both of the hyaluronic acid groups improved with the first injection, and remained significantly better than the placebo group until the end of the survey (p < 0.001). All groups expressed improvement with PGA scores after the first injection. At the end of 6 months all three groups were similar, but the treatment groups were significantly better than the placebo group (p < 0.05), and all were significantly better than at the beginning (p < 0.05). The PhGA scores were similar in all groups until after the third injection. The second group was slightly better in the controls at 1 and 3 months, but all the groups were similar at the end of 6 months. Although the placebo group seemed worse, it was not statistically significant. Compared with lower molecular weight HA, the higher molecular weight HA might be more efficacious in treating knee OA, but heterogeneity of previous studies limited definitive conclusions. Patients treated by injection of either of two hyaluronan preparations showed clinical improvement for pain, though no different from the placebo group; WOMAC stiffness scores were better than placebo in the HA groups, whereas PGA scores showed improvement in all groups but HA groups were better than placebo. PhGA scores were worse in the placebo group, but not to a statistically-significant extent. The HA groups did not differ in terms of clinical efficacy.     

妊娠期肝内胆汁淤积症女性使用熊去氧胆酸治疗与安慰剂比较:一项随机对照试验

【据《Lancet》2019 年9 月报道】题:妊娠期肝内胆汁淤积症女性使用熊去氧胆酸治疗与安慰剂比较:一项随机对照试验(作者Chappell LC 等)妊娠期肝内胆汁淤积症的特征是产妇瘙痒和血清胆汁酸浓度升高,与死产、早产和新生儿入院率增加有关。熊去氧胆酸是被广泛应用的治疗方法,但是没有充分的证据基础。     

Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial

BACKGROUND: Proinflammatory cytokines, especially tumour necrosis factor alpha (TNF-alpha), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-alpha synthesis, may represent a novel and rational approach to the treatment of cancer cachexia. AIMS: To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer. METHODS: Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double blind, randomised controlled trial. The primary outcome was change in weight and nutritional status. RESULTS: Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients (eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had gained on average 0.37 kg in weight and 1.0 cm(3) in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference -2.59 kg (95% confidence interval (CI) -4.3 to -0.8); p = 0.005) and 4.46 cm(3) (absolute difference -5.6 cm(3) (95% CI -8.9 to -2.2); p = 0.002) in the placebo group. At eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm(3) in AMA compared with a loss of 3.62 kg (absolute difference -3.57 kg (95% CI -6.8 to -0.3); p = 0.034) and 8.4 cm(3) (absolute difference -7.9 cm(3) (95% CI -14.0 to -1.8); p = 0.014) in the placebo group. Improvement in physical functioning correlated positively with weight gain (r = 0.56, p = 0.001). CONCLUSION: Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass in patients with cachexia due to advanced pancreatic cancer.