A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. alpha1-Proteinase inhibitor therapy for the prevention of chronic lung disease of prematurity: a randomized, controlled trial. alpha-Interferon in the treatment of chronic viral hepatitis: effects on fibrogenesis serum markers. Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study. Peginterferon alpha-2a combination therapies in chronic hepatitis C patients who relapsed after or had a viral breakthrough on therapy with standard interferon alpha-2b plus ribavirin: a pilot study of efficacy and safety. Interferon alpha plus ketoprofen or interferon alpha plus ribavirin in chronic hepatitis C non-responder to interferon alpha alone: results of a pilot study.
We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr. Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation. Owing to the limited efficacy of therapy on melanoma at the stage of distant metastases, a well-tolerated adjuvant therapy is needed for patients with high-risk primary melanoma. Our hypothesis was that an adjuvant treatment with low doses of interferon alpha could be effective in patients with localised melanoma.
                After resection of a primary cutaneous melanoma thicker than 1.5 mm, patients without clinically detectable node metastases were randomly assigned to receive either 3x10(6) IU interferon alpha-2a, three-times weekly for 18 months, or no treatment. The primary endpoint was the relapse-free interval.
                499 patients were enrolled, of whom 489 were eligible. When used as part of a sequential procedure, interferon alpha-2a was of significant benefit for relapse-free interval (p=0.038). A long-term analysis, after a median follow-up of 5 years, showed a significant extension of relapse-free interval (p=0.035) and a clear trend towards an increase in overall survival (p=0.059) in interferon alpha-2a-treated patients compared with controls. There were 100 relapses and 59 deaths among the 244 interferon alpha-2a-treated patients compared with 119 relapses and 76 deaths among the 245 controls. The estimated 3-year-relapse rates were 32% in the interferon alpha-2a group and 44% in controls; the 3-year death rates were 15% and 21%, respectively. Only 10% of patients experienced WHO grade 3 or 4 adverse events. Treatment was compatible with normal daily life.
                Adjuvant therapy of high-risk melanoma with low doses of interferon alpha-2a for 18 months is safe and is beneficial when started before clinically detectable node metastases develop. A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy.
                Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed.
                After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group.
                Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.
                Copyright 2005 Massachusetts Medical Society. An imbalance between increased neutrophil elastase and a decreased antiprotease shield has been suggested as a factor contributing to the development of chronic lung disease (CLD). We hypothesized that administration of alpha1-proteinase inhibitor (A1PI), also known as alpha1-antitrypsin, to premature neonates would prevent CLD.
                A randomized, placebo-controlled, prospective study of A1PI supplementation was performed. Neonates <24 hours of age with birth weights 600-1000 g on respiratory support, and 1001-1250 g with respiratory distress syndrome (RDS) were eligible. Intravenous A1PI (60 mg/kg) or placebo was infused on days 0, 4, 7, and 14. Primary outcome was CLD in survivors, defined as the need for supplemental oxygen on day 28.
                A total of 106 patients were recruited. There were no significant differences between groups in birth weight or incidence of RDS. The incidence of CLD in survivors was lower in the treated group, but the difference did not reach statistical significance (relative risk [RR], 0.79; confidence interval [CI], 0.60-1.02). This beneficial trend persisted at 36 weeks corrected gestational age (RR, 0.48; CI, 0.23-1.00). The incidence of pulmonary hemorrhage was lower in the treated group (RR, 0.22; CI, 0.05-0.98). Other complications were not significantly different between groups.
                In this, the first trial of a protease inhibitor for the prevention of CLD in premature infants, the infusions were well-tolerated. A1PI therapy may impede the development of CLD and appears to reduce the incidence of pulmonary hemorrhage in some neonates born prematurely. Forty patients with chronic viral hepatitis or active cirrhosis (33 anti-HCV positive) entered a recombinant human alpha 2A interferon randomized trial. Twenty-one subjects were treated with 6 million units (MU) three times per week for 6 months. Nineteen were not treated. Six months later in 12 patients of the treated group (60% of the evaluable 20) with normalized serum aminotransferases levels (responders), fibrogenesis serum markers (NPIIIP and laminin) were significantly lower than baseline. In the untreated patients and in non-responders NPIIIP and laminin were unchanged. Semi quantitative histological evaluation (allotting scores for inflammation, necrosis and fibrosis) confirmed a significant improvement of necro-inflammation in the responders. These data suggest that alpha-IFN treatment may decrease stimuli for fibrogenesis by reducing liver inflammation and necrosis, thus preventing evolution to cirrhosis. After non-response to the initial course of therapy, retreatment with alpha-interferon is not effective. The aim of this study was to ascertain whether the administration of N-acetyl cysteine and vitamin E could increase the response rate to retreatment with alpha-interferon.
                Prospective, multicentre clinical trial.
                Twelve hospitals in Lombardy, Italy.
                120 consecutive patients affected by biopsy-proven chronic hepatitis C who had been non-responders to a previous course of alpha-interferon, administered at the dosage of 3-6 million units (MU) three times a week (tiw) for 6 months.
                The patients were randomly assigned to one of two groups of treatment: group A, natural interferon-alphaN3, 6 or 9 MU tiw, when the body weight was < 60 kg or > or = 60 kg, respectively; group B, the same dosage of natural interferon-alphaN3 in association with oral administration of N-acetyl cysteine 1200 mg/day and vitamin E 600 mg/day. The period of treatment was 6 months in both groups.
                Neither end-therapy biochemical response nor sustained biochemical response rates were improved by the combination treatment, and in no case was clearance of the virus from serum observed.
                In this randomized study carried out on 120 patients with chronic hepatitis C not responsive to alpha-interferon, oral supplementation with N-acetyl cysteine and vitamin E did not improve the poor efficacy of retreatment with alpha-interferon alone. There are no established therapeutic regimens for hepatitis C virus (HCV) patients who relapse following treatment with interferon alpha-2b and ribavirin or those who break through while on interferon alpha-2b and ribavirin. We therefore evaluated various combination therapies in HCV patients who relapsed or experienced a viral breakthrough. Patients (n = 124) were randomized to 48 weeks of treatment with once-weekly subcutaneous injections of 180 microg pegylated (peg-) interferon alpha-2a plus oral ribavirin (800-1000 mg/day), mycophenolate mofetil (2 g/day), amantadine (200 mg/day), or ribavirin and amantadine and followed for an additional 24 weeks. The sustained virologic response was higher in patients administered peginterferon alpha-2a plus ribavirin (38%) or ribavirin and amantadine (45%) than in those administered peginterferon alpha-2a plus mycophenolate mofetil (17%) or amantadine (10%). As in previous studies, patients with genotype non-1 and those with lower viral loads had better responses than those with genotype 1 and high viral loads, though the differences did not reach significance. The four treatment regimens had similar safety profiles, except that patients receiving ribavirin had greater maximal hemoglobin decreases. These findings suggest that the combination of peginterferon alpha-2a plus ribavirin or with ribavirin and amantadine is effective in some HCV patients who relapse after treatment with interferon alpha-2b plus ribavirin. Recently, in vitro and in vivo studies demonstrated that non-steroidal anti-inflammatory drugs are able to enhance the activity of interferon alpha.
                To evaluate the efficacy and tolerability of ketoprofen (a non-steroidal anti-inflammatory drug) plus interferon alpha (group B) compared to interferon alpha plus ribavirin (group C) and interferon alpha alone (group A) in chronic hepatitis C non-responders after a 5-month course with interferon alpha.
                Without stopping interferon alpha, 49 patients were randomized to receive one of the three treatment regimens for 4 months.
                Three patients discontinued the therapy. One out of 16 patients in group A, 6/16 in group B and 5/14 in group C, alanine aminotransferase returned to normal at the end of the therapies (B vs A: p=0.04); serum hepatitis C virus-RNA became negative in 1 patient in group A and in 4 patients in both group B and group C. Six months after treatment, normal alanine transferase and negative hepatitis C virus-RNA were observed in 3 patients in group B and 2 in group C. In these patients, liver histology significantly improved.
                These results indicate that a certain number of non-responder patients to interferon alpha can benefit from a combination therapy of interferon alpha plus ketoprofen that is at least as effective as the combination interferon alpha plus ribavirin.
Augmentation therapy with alpha-1 antitrypsin cannot be recommended, in view of the lack of evidence of clinical benefit and the cost of treatment.