A randomized, double-blind, placebo-controlled trial on restenosis prevention by the receptor tyrosine kinase inhibitor imatinib.

OBJECTIVES: The aim of the present double-blind, placebo-controlled study was to evaluate the efficacy of a systemic imatinib treatment, a potent platelet-derived growth factor (PDGF) receptor kinase inhibitor, for the prevention of recurrent restenosis in patients with in-stent restenosis (ISR). BACKGROUND: Neointima proliferation after stent placement has been associated with the effect of potent mitogenes such as PDGF, and their inhibition has resulted in reduction of neointima formation in experimental models. METHODS: A total of 180 patients with either symptoms or a positive stress test in the presence of angiographically significant ISR were randomly assigned to two treatment arms: imatinib treatment or placebo. Patients received imatinib (600 mg/day) for 10 days starting 2 days before repeat intervention. Angiographic restenosis at follow-up angiography was the primary end point of the study. RESULTS: Repeat angiography was performed in 160 of 180 patients (88.9%). The combined rate of death or MI at one year was 1.0% in patients randomized to either group (p = 0.67). Compared with the placebo group, imatinib treatment did not affect the angiographic restenosis rate (38.8% with imatinib vs. 41.3% with placebo; p = 0.75). Similarly, the need for target lesion revascularization did not differ between both groups (28.1% with imatinib vs. 28.6% with placebo; p = 0.94). CONCLUSIONS: Systemic imatinib therapy does not affect the risk of recurrence in patients with ISR.     

Transdermal clonidine in mild hypertension. A randomized, double-blind, placebo-controlled trial

In 30 patients with mild essential hypertension, clonidine hydrochloride was delivered from a skin patch reservoir designed to release medication at a constant rate for seven days. After a four-week washout period, patients were randomized (double-blind) into a clonidine- or a placebo-treated group. Clonidine or placebo was then given for five weeks, followed by a two-week washout period to assess withdrawal from treatment. Blood pressure was controlled in 11 of 15 clonidine-treated patients but in only four of 15 placebo-treated patients. The clonidine-treated group evidenced larger decreases in both systolic and diastolic blood pressures. In the clonidine-treated group, blood pressures and plasma clonidine levels were stable throughout a representative seven-day period. Besides mild skin irritation with both clonidine and placebo patches, few side effects were observed. After discontinuation of clonidine administration, plasma levels declined in a non-log linear manner. There was no rebound hypertension. The results suggest that clonidine delivered transdermally is safe and effective for control of mild essential hypertension.     

The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial

BACKGROUND: Epidemiologic studies, studies of mechanisms of action, and many animal studies indicate that dietary intake of omega-3 fatty acids has antiatherosclerotic potential. Few trials in humans have examined this potential. OBJECTIVE: To determine the effect of dietary intake of omega-3 fatty acids on the course of coronary artery atherosclerosis in humans. DESIGN: Randomized, double-blind, placebo-controlled, clinically controlled trial. SETTING: University preventive cardiology unit. PATIENTS: 223 patients with angiographically proven coronary artery disease. INTERVENTION: Fish oil concentrate (55% eicosapentaenoic and docosahexaenoic acids) or a placebo with a fatty acid composition resembling that of the average European diet, 6 g/d for 3 months and then 3 g/d for 21 months. MEASUREMENTS: The results of standardized coronary angiography, done before and after 2 years of treatment, were evaluated by an expert panel (primary end point) and by quantitative coronary angiography. Patients were followed for clinical and laboratory status. RESULTS: Pairs of angiograms (one taken at baseline and one taken at 2 years) were evaluated for 80 of 112 placebo recipients and 82 of 111 fish oil recipients. At the end of treatment, 48 coronary segments in the placebo group showed changes (36 showed mild progression, 5 showed moderate progression, and 7 showed mild regression) and 55 coronary segments in the fish oil group showed changes (35 showed mild progression, 4 showed moderate progression, 14 showed mild regression, and 2 showed moderate regression) (P = 0.041). Loss in minimal luminal diameter, as assessed by quantitative coronary angiography, was somewhat less in the fish oil group (P > 0.1). Fish oil recipients had fewer cardiovascular events (P = 0.10); other clinical variables did not differ between the study groups. Low-density lipoprotein cholesterol levels tended to be greater in the fish oil group. CONCLUSION: Dietary intake of omega-3 fatty acids modestly mitigates the course of coronary atherosclerosis in humans.     

Adalimumab in the treatment of chronic pouchitis. A randomized double-blind,placebo-controlled trial

Background: Pouchitis is a complication of ileal pouch-anal anastomosis and occurs in up to 50% of patients 10 years after IPAA with 10% developing refractory pouchitis.

Objective: To evaluate the effect of a TNF-α inhibitor (Adalimumab) in the treatment of refractory pouchitis.

Materials and methods: A multicenter, randomized double-blind, placebo-controlled trial includes patients with refractory pouchitis for more than 4 weeks despite antibiotic treatment. Patients were randomized to Adalimumab or placebo for 12 weeks. Primary outcome was reduction in clinical pouchitis disease activity index (PDAI) of ≥2 at any time. Secondary endpoints were remission of pouchitis, endoscopic and histologic effect and quality of life.

Results: Thirteen patients were included; six patients received active treatment and seven patients received placebo. Nine patients (5/4, Adalimumab/placebo) completed the 12-week program. Reduction in clinical PDAI ≥ 2 was achieved in three patients in each group (50%/43%, Adalimumab/placebo, p?>?.5). Total PDAI improved in six patients treated with Adalimumab and two patients on placebo (100%/29%, p?=?.13). There were no differences in secondary endpoints between the groups.

Conclusions: In this randomized controlled trial of treatment with Adalimumab in patients with refractory pouchitis, we were not able to identify any clinical benefit in the primary or secondary endpoints.     

Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial

BACKGROUND: Among persons who receive solid organ transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective. OBJECTIVE: To evaluate the efficacy and safety of prophylactic fluconazole in liver transplant recipients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-affiliated transplantation center. PATIENTS: 212 liver transplant recipients who received fluconazole (400 mg/d) or placebo until 10 weeks after transplantation. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, drug-related side effects, and death. RESULTS: Fungal colonization increased in patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003). CONCLUSIONS: Prophylactic fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.     

A double-blind,placebo-controlled trial

Sulfasalazine (SSZ), 3 gm daily, was compared with placebo for treatment of rheumatoid arthritis, in a 15-week randomized, parallel, double-blind trial. Joint tenderness and swelling, morning stiffness, grip strength, and pain score all showed significantly more improvement with SSZ than with placebo. Adverse effects, particularly gastrointestinal reactions, led to withdrawal from the study of 28% of the patients who had been receiving SSZ, but these effects were all readily reversible and not life-threatening. These results confirm previous findings that suppression of rheumatoid synovitis may be induced by SSZ, within 2 months after full maintenance doses are reached.     

Efficacy of influenza vaccination in HIV-infected persons. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although influenza vaccination is recommended in persons infected with HIV-1, its efficacy is unknown. OBJECTIVE: To assess the immunogenicity, efficacy, and risks associated with influenza vaccination in persons infected with HIV-1. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Outpatient military clinic. PATIENTS: 102 patients with HIV-1 infection. INTERVENTION: Influenza vaccine (n = 55) or saline placebo (n = 47). MEASUREMENTS: Influenza antibody titers, CD4+ cell counts, and plasma HIV-1 RNA levels at baseline, 1 month after immunization, and 3 months after immunization; viral cultures from persons presenting with respiratory illness; and respiratory symptom interview. RESULTS: Twenty-three placebo recipients (49%) and 16 vaccine recipients (29%) reported respiratory symptoms (P = 0.04). Ten placebo recipients but no vaccine recipients had laboratory-confirmed symptomatic influenza (P < 0.001) (protective efficacy, 100% [95% CI, 73% to 100%]). No effect on plasma HIV-1 RNA levels or CD4+ cell counts was noted. CONCLUSION: Influenza vaccination is highly effective in HIV-1-infected persons and does not seem to be associated with substantial changes in viral load or CD4 cell count.     

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial

BACKGROUND: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. OBJECTIVE: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma. DESIGN: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. SETTING: Academic referral centers. PATIENTS: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. INTERVENTION: Recombinant human relaxin, 25 or 100 microg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. MEASUREMENTS: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. RESULTS: Patients who received 25 microg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 microg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). CONCLUSIONS: Twenty-four weeks of recombinant human relaxin, 25 microg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.     

A dietary fibre supplement in the treatment of mild hypertension. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To study the effects of a dietary fibre supplement given as monotherapy upon blood pressure in mildly hypertensive patients. DESIGN: The investigation was performed as a prospective randomized, double-blind, placebo-controlled trial for 3 months. SETTING: Patients attending an outpatient hypertension clinic in a hospital. PATIENTS: Hypertensive patients with a minimum of two diastolic blood pressure (DBP) readings greater than 90 mmHg during a 2-week run-in period were included. Of the 65 patients enrolled, 63 were randomized (32 fibre, 31 placebo). Six patients did not complete the trial. INTERVENTION: Patients were treated with either fibre (7 g/day) or matching placebo. MAIN OUTCOME MEASURE: Based on previous studies, the a priori hypothesis was that dietary fibre supplementation could reduce blood pressure in hypertensive patients. RESULTS: Body weight was significantly reduced in the fibre group. Dietary fibre significantly reduced DBP and fasting serum insulin. However, no correlation between changes in body weight and systolic blood pressure or DBP was found. CONCLUSION: A dietary fibre supplement can lower DBP in mildly hypertensive patients independent of changes in body weight.     

Nutritional supplementation of elderly hip fracture patients. A randomized, double-blind, placebo-controlled trial

BACKGROUND: undernourishment is common in elderly hip fracture patients and has been linked to poorer recovery and increased post-operative complications. OBJECTIVE: to determine whether a nutritional supplement may (i) help elderly patients return to pre-fracture functional levels 6 months post-fracture and (ii) decrease fracture-related complications and mortality. DESIGN: a double-blind, randomized, placebo-controlled clinical trial. SETTING: a county hospital near Barcelona. SUBJECTS: 171 patients, aged 70 and older, hospitalized for hip fracture between July 1994 and July 1996. METHODS: we randomized patients to intervention (n = 85) or control (n = 86) group. Patients received a nutritional supplement containing 20 g of protein and 800 mg of calcium or placebo for 60 days. We determined functional levels by the Barthel index, the mobility index and by the use of walking aids. We performed assessments during hospitalization and at 2 and 6 months post-fracture. FINDINGS: the two groups were comparable at study entry. We observed no differences in return to functional status 6 months post-fracture (61% intervention group vs 55% in control group) nor in fracture-related mortality (13% in intervention group vs 10% in control group). The intervention group suffered fewer in-hospital [odds ratio 1.88 (95% CI 1.01 - 3.53), P = 0.05] and total complications [odds ratio 1.94 (95% CI 1.02-3.7), P = 0.04] than the control group. CONCLUSION: based on our results, we cannot recommend routine nutritional supplementation of all elderly hip fracture patients. While nutritional supplementation may be useful in decreasing complications, this reduction does not result in improvement in functional recovery and nor does it decrease fracture-related mortality. Selected patients may, however, benefit from nutritional supplementation.     

A double-blind,randomized, placebo-controlled trial of prostaglandin E1 in liver transplantation

A double-blind placebo-controlled trial of intravenous prostaglandin PGE₁ (40 μg/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE₁; 82 placebo). Patient and graft survival were similar (PGE₁: 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE₁ administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE₁: 24.4 days; controls: 31.8 days; P = .02) and a 40% shorter length of time postoperatively in the intensive care unit (PGE₁: 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support (P = .03) or surgical intervention other than retransplantation (P = .02) were also noted with PGE₁ use. Further, PGE₁ administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE₁ administration, (PGE₁: 9; controls: 4). These results suggest that PGE₁ use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions.     

A randomized, double-blind, placebo-controlled trial of nutritional supplementation during acute illness

Purpose

The study tested whether nutritional support of older patients during acute illness leads to a clinical benefit.

Methods

In this randomized, double-blind, placebo-controlled study, we randomly assigned 445 hospitalized patients aged 65 to 92 years to receive either a normal hospital diet plus 400 mL oral nutritional supplements (223 subjects) or a normal hospital diet plus a placebo (222 subjects) daily for 6 weeks. The composition of the supplement was such as to provide 995 kcal of energy and 100% of the Reference Nutrient Intakes for vitamins and minerals for a healthy older person. Patients had three assessments: at baseline, at 6 weeks, and at 6 months post-randomization. Outcome measures were 6 months of disability, non-elective readmission and length of hospital stay, discharge destination, morbidity, and mortality.

Results

Randomization to the supplement group led to a significant improvement in nutritional status. Over 6 months, 65 patients (29%) in the supplements group were readmitted to the hospital compared with 89 patients (40%) in the placebo group (adjusted hazard ratio 0.68 [95% confidence interval 0.49-0.94]). The mean length of hospital stay was 9.4 days in the supplements group compared with 10.1 days in the placebo group. Thirty-two people (14%) died in the supplement group compared with 19 people (9%) in the placebo group at 6 months (adjusted hazard ratio 1.65 [95% confidence interval, 0.93-2.92]).

Conclusion

Oral nutritional supplementation of acutely ill patients improved nutritional status and led to a statistically significant reduction in the number of non-elective readmissions.     

A randomized,double-blind,placebo-controlled trial of infliximab in refractory polymyositis and dermatomyositis

ObjectiveTo investigate in a pilot study the safety and efficacy of infliximab in patients with refractory dermatomyositis (DM) and polymyositis (PM).MethodsA randomized, double-blind, placebo-controlled trial including subjects with active DM or PM. Participants had stable doses of immunosuppressive medication and prednisone (≤0.5 mg/kg/day), and exhibited clinical signs of muscle weakness for at least 4 weeks prior to study entry. Participants received infusions of either placebo or infliximab 5 mg/kg at 0, 2, 6, and 14 weeks in blinded manner. The primary outcome was a ≥15% manual muscle strength (MMT) improvement at week 16 compared to week 0. The secondary outcome measures were improvement defined by the International Myositis Assessment and Clinical Studies Group (IMACS) criteria. At week 16, responders in each arm had the option of either continuing the same treatment or changing to the non-responder treatment for that study arm. Non-responders in the 5 mg/kg infliximab arm were increased to infliximab 7.5 mg/kg for weeks 22, 30, and 38. Non-responders in the placebo arm at week 16 received infliximab 5 mg/kg at weeks 16, 18, 22, 30, and 38. Outcomes were reassessed at week 40.ResultsTwelve subjects completed the study to week 16. Six of the 12 subjects received infliximab treatment at the dose of 5 mg/kg with only one subject meeting the responder criteria at that dose. Of the remaining five subjects on infliximab, three crossed over to the infliximab 7.5 mg/kg dose. One of those three subjects responded. All six patients in the placebo arm crossed over to the 5 mg/kg dosing regimen after week 16, and two of those responded to infliximab.ConclusionsInfliximab therapy for patients with refractory PM and DM was well tolerated and may benefit a subset of patients.     

Slow-release lanreotide in Graves' ophthalmopathy: A double-blind randomized, placebo-controlled clinical trial

SS analogs are an attractive alternative in treating Graves' ophthalmopathy (GO). Most of the previous studies were uncontrolled and enrolled few patients. The present study was conducted as a larger scale, prospective, randomized controlled study to determine the effectiveness of a slow-release formulation of lanreotide in GO. Sixty patients with active GO received an im injection every two weeks of either lanreotide 30 mg or placebo for 12 weeks. They were then followed and further treated in the traditional way if necessary. The Clinical Activity Score (CAS) was the primary efficacy criterion. Proptosis, diplopia, corneal erosion or ulcer, visual acuity, extraocular muscle movement and intraocular pressure were also evaluated. At the end of the 12 weeks, the mean CAS was not significantly decreased in the lanreotide group compared to the placebo group. The overall mean difference of proptosis between these two groups also did not reach significance at 12 weeks. Only diplopia at downward gaze had significant improvement for the lanreotide- treated group vs placebo group (p = 0.03). No differences were observed between the two groups compared to other outcome measures. During the 24-month follow-up after the clinical trial, 14 patients received eye surgery in the placebo group compared with 10 patients in the lanreotide group (p = 0.29). Six patients received methylprednisolone pulse therapy in the placebo group and two patients in the lanreotide group (p = 0.25). In conclusion, lanreotide treatment had no significant effects on GO compared with placebo.     

Effects of rosuvastatin on vascular biomarkers and carotid atherosclerosis in lupus: a randomized, double-blind, placebo-controlled trial

Objective

To study the effect of rosuvastatin on vascular biomarkers and carotid intima‐media thickness (IMT) in systemic lupus erythematosus (SLE).

Methods

SLE patients with inactive disease and subclinical atherosclerosis were randomized in a double‐blinded manner to receive either rosuvastatin (10 mg/day) or matching placebo (half in each group were also randomly allocated low‐dose aspirin). After 12 months, treatment was unblinded. Patients treated with rosuvastatin and aspirin were continued on the same medications for another 12 months. Plasma levels of homocysteine, high‐sensitivity C‐reactive protein (hsCRP), soluble vascular cell adhesion molecule 1, P‐selectin, and thrombomodulin were measured at baseline, 6 months, and 12 months. Measurement of carotid IMT was repeated at 24 months.

Results

Seventy‐two patients were studied (97% women, mean ± SD age 50.8 ± 9.7 years). Thirty‐six patients were randomly assigned to each of the study arms (18 patients in each arm also received aspirin). Baseline clinical characteristics and medications were similar between the two groups. At 12 months, the mean low‐density lipoprotein cholesterol (mean ± SD 2.62 ± 1.04 mmoles/liter to 1.69 ± 0.72 mmoles/liter; P < 0.001) and median hsCRP levels (1.26 mg/liter, interquartile range [IQR] 2.3 to 0.88 mg/liter, IQR 1.1; P = 0.02) decreased significantly in the rosuvastatin group. There was no significant change in homocysteine, and aspirin use did not influence the levels of the biomarkers studied. A subgroup analysis of patients with a Systemic Lupus Erythematosus Disease Activity Index score ≤2 revealed a significant decrease in hsCRP (1.20 mg/liter, IQR 2.3 to 0.92 mg/liter, IQR 1.1; P = 0.04) and thrombomodulin levels (0.76 ng/ml, IQR 1.2 to 0.67 ng/ml, IQR 1.0; P = 0.001) with rosuvastatin treatment. At 24 months, the IMT of the internal carotid arteries appeared to be decreased in patients treated with rosuvastatin, which was well tolerated.

Conclusion

In stable SLE patients, low‐dose rosuvastatin leads to a significant reduction in hsCRP and thrombomodulin levels, which may possibly help to reduce cardiovascular risk.     

Tapering of corticosteroid therapy following exacerbation of asthma. A randomized, double-blind, placebo-controlled trial

Systemic corticosteroids are effective in the treatment of acute asthma, but the optimal schedule for steroid withdrawal following an asthma exacerbation has not been determined. This study was designed to test the hypothesis that tapering the corticosteroid dosage over a longer period of time reduces the number of reexacerbations. Non-steroid-dependent adult men hospitalized for asthma exacerbations during a one-year period (n = 43) were randomly assigned to corticosteroid tapering regimens of one or seven weeks, following an eight-day course of high-dose corticosteroid therapy. There were no significant differences between the long-taper and short-taper groups in rate of reexacerbation (41% vs 52%) or readmission (22% vs 21%) during the 12-week study period. Patients who did not have a reexacerbation during the 12 weeks were evaluated with spirometry, with no significant differences occurring between the two groups. More patients in the long-taper group reported corticosteroid side effects (41% vs 14%). Patients who required mechanical ventilation during the initial hospitalization (n = 7), or who reported more than two days of worse than usual dyspnea in the 12-week period (n = 20), had high rates of reexacerbation (86% and 80%, respectively). These results provide reasonable certainty (90%) that a long taper does not result in a large reduction (50% or more) in reexacerbations compared with a short taper. We conclude that the relapse rate is high in this population regardless of the corticosteroid tapering regimen used, and that a long taper does not appear to provide enough benefit to justify its routine use.