A double-blind,placebo-controlled,pilot trial of thymosin alpha 1 for the treatment of chronic hepatitis C

Abstract: A randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy and safety of thymosin alphal (α₁) in treating chronic hepatitis C. Nineteen Italian patients with chronic active hepatitis C, proven by biopsy were randomly assigned to receive a six month course of thymosin α₁ (900 μg/m² of body surface area twice weekly) or a placebo. All had HCV-RNA in their serum (by PCR), with serum ALT levels more than double the upper limit of the normal range for at least six months before enrollment. After treatment, patients were followed for an additional six months. All patients completed the trial. One patient treated with thymosin α₁, but no patient in the placebo group, normalized serum ALT levels by the end of the treatment. This patient, however, relapsed at the sixth month of the follow-up. Overall, there were no significant changes in mean serum ALT levels in either group during the treatment or follow-up period. No patient cleared HCV-RNA. No side effects were reported except for local discomfort at the injection sites, reported by some patients treated with thymosin α₁. In conclusion, this regimen of thymosin α₁ is not effective in the treatment of chronic hepatitis C.     

Ranitidine in reflux oesophagitis. A double-blind placebo-controlled study

This study was designed to assess the effect of ranitidine on patients with symptomatic oesophageal reflux. In a double-blind comparative trial in 46 patients a twice daily dose of 150 mg ranitidine was compared with placebo. Relief of pain, endoscopic healing and histological improvement were significantly better in those treated with ranitidine. Thus, ranitidine is of value in the management of patients with reflux oesophagitis and may prevent the development of peptic stricture.     

Ketanserin in intermittent claudication. A double-blind placebo-controlled study

Twenty patients with intermittent claudication and having an ankle/arm blood pressure ratio less than or equal to 0.75 were randomized to receive ketanserin 40 mg b.i.d. or placebo for three months under double-blind conditions following a six-week run-in period. A placebo was administered for an additional six weeks at the end of the double-blind phase. Results indicated that ketanserin significantly increased (p less than 0.04) the pain-free walking distance by 36% versus a non-significant 10% rise with placebo. During the run-out period, this parameter remained significantly increased (p less than 0.04) with ketanserin. Changes in the total walking distance during the double-blind period were 15% and 11% for ketanserin and placebo, respectively, with a significant (p less than 0.05) increase to 30% occurring in the ketanserin group during the run-out phase. There was a decrease in the ankle/arm blood pressure ratio in the worst leg in both groups. The rise of systemic blood pressure after exercise was attenuated with ketanserin. Side-effects were reported in only one patient in the placebo group. These data indicate that ketanserin may be of value in patients suffering from intermittent claudication. Other studies are, however, warranted to determine whether this beneficial effect is general or restricted to a subgroup of patients.     

A randomized placebo-controlled double-blind study of danazol in hemophilia A.

A randomized double-blind placebo-controlled crossover trial of danazol was carried out in 19 cases of hemophilia A. Danazol was given for 3 months at a dose of 150 mg/day to patients under 15 years of age, and 300 mg/day to older patients. The basal factor VIII:C level was 8.3 +/- 5.6% (mean +/- SD), and after 3 months of danazol treatment was 15.3 +/- 11.0% (p = 0.02). Six patients (basal factor VIII:C 2-22%) showed a 1.36- to 2.87-fold elevation of factor VIII:C levels after danazol. 0/2, 1/4 and 5/13 cases of severe, moderate and mild disease, respectively, responded. Decreases in the number of bleeding episodes and cryoprecipitate requirement were seen in the responders. No adverse reactions to danazol were encountered. Danazol appears to raise the factor VIII:C levels in selected cases of hemophilia A.     

Treatment of external genital warts in men with imiquimod 2% in cream. A placebo-controlled, double-blind study

OBJECTIVE: The purpose of this double-blind, placebo-controlled study was to evaluate the safety, clinical efficacy and tolerability of imiquimod (2%) in cream to cure external genital warts in males. METHODS: Preselected male patients (n=60) ranging between 18 and 50 years of age (mean 24.2) harbouring 558 lesions (mean 9.3) with clinical, histopathological and polymerase chain reaction (PCR) confirmed diagnosis of human papilloma virus (HPV) infection were randomized to two parallel groups. Each patient was allocated a precoded 25g tube, and instructions on how to apply the trial medication to their lesions at home once daily for three consecutive days per week (max. 12 application in 4 weeks). To evaluate the safety, clinical efficacy and tolerance, patients were exa-mined on a weekly basis. Cure was defined as the total elimination of treated warts with PCR, and Southern blot hybridization confirmed negative HPV DNA. RESULTS: By the end of the treatment, 40% (24/60) patients and 49.8% (278/558) warts were cured. Breaking the code revealed that imiquimod cream had cured 70% (21/30) patients and 86.8% of warts, while placebo healed three subjects and 28 warts (P=0.0001). Eleven patients (18.3%), predominantly in the imiquimod cream group, experienced mild to moderate, non-objective, drug-related side effects with no dropouts. The study was followed up for 18 months from the first day of the treatment, and among the 26 cured patients, one in the imiquimod cream group and two in the placebo had a relapse after 14 months. CONCLUSION: The study demonstrated that 2% imiquimod in cream with mild non-objective side effects is safe, tolerable and significantly more effective than placebo in curing external genital warts in males.     

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.     

Evaluation of amitriptyline in primary fibrositis. A double-blind, placebo-controlled study

Seventy patients with primary fibrositis satisfying Smythe's criteria were studied in a 9-week double-blind trial comparing 50 mg amitriptyline with placebo. Fifty-nine patients completed the trial: 27 were treated with amitriptyline, and 32 took a placebo. The patients who received amitriptyline improved significantly in their morning stiffness and pain analog scores at 5 and 9 weeks, compared with baseline scores, whereas no changes were noted in these parameters in the placebo group. Fibrocytic point tenderness did not improve significantly in either of the treatment groups. When compared with the placebo group, the amitriptyline group improved significantly with respect to sleep pattern and patient and physician global assessments. Our data indicate that amitriptyline has some therapeutic benefit in patients with primary fibrositis.     

IX 207-887 in rheumatoid arthritis. A double-blind placebo-controlled study.

OBJECTIVE. To determine the efficacy and the safety of IX 207-887 treatment in rheumatoid arthritis. The IX compound [10-methoxy-4H-benzo(4,5)cyclohepta-(1,2-b)thiophene-4-yliden acetic acid] is effective in several animal models of rheumatoid arthritis and has a mechanism of action involving the inhibition of interleukin-1 release. METHODS. A double-blind, controlled trial of 16 weeks' duration comparing placebo with IX at a daily dosage of 800 mg or 1,200 mg (20 patients/group) was conducted. RESULTS. Thirteen patients withdrew from the study, 3 because of lack of efficacy (all in the placebo group) and 10 because of side effects (1 in the placebo group [skin rash] and 9 in the IX groups [skin rash in 5, intestinal disturbances in 2, hepatitis in 1, meningitis in 1]). Intent-to-treat analysis showed a statistically significant difference in the variations of clinical and laboratory parameters between the 3 groups. Between-group comparisons showed an improvement in all these variables in the IX groups versus the placebo group. According to Paulus' criteria, 2 of the 20 placebo-treated patients (10%), 9 of the 20 IX 800 mg-treated patients (45%), and 11 of the 20 IX 1,200 mg-treated patients (55%) were considered responders (P = 0.008). CONCLUSION. The findings of this study suggest that the tolerability of IX is acceptable in rheumatoid arthritis patients, and that IX is an effective slow-acting drug for use in rheumatoid arthritis.     

A randomized,double-blind,placebo-controlled study of cd4 monoclonal antibody therapy in early rheumatoid arthritis

Objective. To assess the efficacy of the CD4 monoclonal antibody (MAb) cM-T412 in the treatment of early rheumatoid arthritis (RA). Methods. Sixty patients were enrolled in a 6-week randomized, double-blind, placebo-controlled study investigating multiple dose regimens of cM-T412. Thirty patients subsequently were enrolled in a 9-month randomized, double-blind, placebo-controlled study investigating monthly single-dose administrations of cM-T412. Results. Analysis of clinical parameters revealed no changes in arthritis activity in the groups that received CD4 MAb or the placebo group, and no difference between the groups, in either in the first or the second part of the study. The number of circulating CD4+ cells decreased substantially in the patients treated with CD4 MAb. Conclusion. CD4 MAb treatment of patients with early RA induced no therapeutic effect.     

IX 207-887 in Rheumatoid Arthritis. A double-blind placebo-controlled study

Objective. To determine the efficacy and the safety of IX 207-887 treatment in rheumatoid arthritis. The IX compound [10-methoxy-4H-benzo(4,5)cyclohepta-(1,2-b)thiophene-4-yliden acetic acid] is effective in several animal models of rheumatoid arthritis and has a mechanism of action involving the inhibition of interleukin-1 release. Methods. A double-blind, controlled trial of 16 weeks' duration comparing placebo with IX at a daily dosage of 800 mg or 1,200 mg (20 patients/group) was conducted. Results. Thirteen patients withdrew from the study, 3 because of lack of efficacy (all in the placebo group) and 10 because of side effects (1 in the placebo group [skin rash] and 9 in the IX groups [skin rash in 5, intestinal disturbances in 2, hepatitis in 1, meningitis in 1]). Intent-to-treat analysis showed a statistically significant difference in the variations of clinical and laboratory parameters between the 3 groups. Between-group comparisons showed an improvement in all these variables in the IX groups versus the placebo group. According to Paulus' criteria, 2 of the 20 placebo-treated patients (10%), 9 of the 20 IX 800 mg–treated patients (45%), and 11 of the 20 IX 1,200 mg–treated patients (55%) were considered responders (P = 0.008). Conclusion. The findings of this study suggest that the tolerability of IX is acceptable in rheumatoid arthritis patients, and that IX is an effective slow-acting drug for use in rheumatoid arthritis.     

A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B

BACKGROUND: Emtricitabine is a nucleoside analogue approved for treatment of human immunodeficiency virus 1 with clinical activity against hepatitis B virus (HBV). METHODS: To compare the safety and efficacy of emtricitabine with placebo in patients with HBV, we conducted a randomized (2:1), double-blind study at 34 sites in North America, Asia, and Europe that enrolled adults between November 2000 and July 2002 who had chronic HBV infection but had never been exposed to nucleoside or nucleotide treatment. Each patient received either 200 mg of emtricitabine (n=167) or placebo (n=81) once daily for 48 weeks and underwent a pretreatment and end-of-treatment liver biopsy. Histologic improvement was defined as a 2-point reduction in Knodell necroinflammatory score with no worsening in fibrosis. RESULTS: At the end of treatment, 103 (62%) of 167 patients receiving active treatment had improved liver histologic findings vs 20 (25%) of 81 receiving placebo (P<.001), with significance demonstrated in subgroups positive (P<.001) and negative (P=.002) for hepatitis Be (HBe) antigen. Serum HBV DNA readings showed less than 400 copies/mL in 91 (54%) of 167 patients in the emtricitabine group vs 2 (2%) of 81 in the placebo group (P<.001); alanine aminotransferase levels were normal in 65% (109/167) vs 25% (20/81), respectively (P<.001). At week 48, 20 (13%) of 159 patients in the emtricitabine group with HBV DNA measured at the end of treatment had detectable virus with resistance mutations (95% confidence interval, 8%-18%). The rate of seroconversion to anti-HBe (12%) and HBe antigen loss were not different between arms. The safety profile of emtricitabine during treatment was similar to that of placebo. Posttreatment exacerbation of HBV infection developed in 23% of emtricitabine-treated patients. CONCLUSION: In patients with chronic HBV, both positive and negative for HBe antigen, 48 weeks of emtricitabine treatment resulted in significant histologic, virologic, and biochemical improvement.     

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.     

Long-term clinical effect of nilvadipine in patients with chronic heart failure: A double-blind placebo-controlled study

Summary The long-term effect of calcium channel blockers on chronic heart failure is disappointing, probably because of reflex sympathetic activation through arterial vasodilation. However, nilvadipine may be beneficial for treatment of chronic heart failure since this drug has minimal effects on sympathetic activation. In this study, the effects of 12-week administration of nilvadipine or placebo on symptoms of heart failure and cardiac function were investigated in 23 patients with mild-to-moderate chronic heart failure in a double-blind trial. The patients were randomly assigned to either a nilvadipine group (16 mg daily) or a placebo group. Intergroup comparisons did not show significant differences in any parameters. Serious adverse effects were not observed during the study. Thus, this study failed to show any beneficial effect of nilvadipine in the long-term treatment of patients with chronic heart failure. We conclude that the long-term administration of nilvadipine (16 mg daily) is neither effective nor harmful in the treatment of patients with chronic heart failure.Other members are listed in the appendix.     

A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus.

OBJECTIVE: To determine if dehydroepiandrosterone (DHEA) is beneficial in severe systemic lupus erythematosus (SLE). METHODS: A double-blinded, placebo-controlled, randomized clinical trial in 21 patients with severe and active SLE, manifestated primarily by nephritis, serositis or hematological abnormalities. In addition to conventional treatment with corticosteroids +/- immunosuppressives, patients received DHEA 200 mg/d vs. placebo for 6 months, followed by a 6-month open label period. The primary outcome was a prospectively defined responder analysis, based on a quantitatively specified improvement of the principal severe lupus manifestation at 6 months. RESULTS: Nineteen patients were available for evaluation at 6 months. Baseline imbalance between the groups was noted, with the DHEA group having greater disease activity at baseline (P<0.05 by physician's global assessment). Eleven patients were responders: 7/9 patients on DHEA vs. 4/10 patients on placebo (P<0.10). Of the secondary outcomes, mean improvement in SLE disease activity index (SLE-DAI) score was greater in the DHEA group (-10.3+/-3.1 vs. -3.9+/-1.4. P<0.07). Bone mineral density at the lumbo-sacral spine showed significant reduction in the placebo group, but was maintained in the DHEA group. CONCLUSION: DHEA therapy, when added to conventional treatment for severe SLE, may at most have a small added benefit with respect to lupus outcomes, but baseline imbalances in the study population limit the generalizability of the results. DHEA appears to have a protective effect with respect to corticosteroid-induced osteopenia in such patients.     

A double-blind placebo-controlled study of auranofin in patients with psoriatic arthritis

Two hundred thirty-eight patients with psoriatic arthritis were entered into a 6-month, multicenter, double-blind trial comparing auranofin and placebo. Polyarthritis (greater than 5 tender joints) was present in 90% of the patients, and 94% were seronegative. Auranofin treatment was statistically superior to placebo treatment, according to physician's global assessment and functional scores. A trend in favor of auranofin treatment was seen for each of the other disease parameters studied. Psoriasis worsened in 6 auranofin-treated patients and in 3 placebo-treated patients. The incidence and nature of other side effects were similar to those observed in similar trials of patients with rheumatoid arthritis. Our observations suggest that the use of auranofin in the treatment of psoriatic arthritis is safe, although its therapeutic advantage over treatment with nonsteroidal antiinflammatory drugs alone is modest.     

EDTA treatment of intermittent claudication--a double-blind, placebo-controlled study.

A double-blind, randomized multicentre study was undertaken to evaluate the possible effect of chelation treatment with ethylenediamine-tetraacetic acid (EDTA) in patients with severe intermittent claudication. A total of 153 patients received 20 intravenous infusions of either 3 g Na2EDTA or placebo during a period of 5-9 weeks. Vitamin, mineral and trace element supplements were administered orally. The changes observed in the pain-free and maximal walking distances, measured on a treadmill, were similar in the two groups. During the 3-month (n = 149) and 6-month (n = 123) follow-up period, no long-term therapeutic effect of EDTA could be demonstrated. The ankle-brachial blood pressure index remained unchanged throughout the study period. This study failed to demonstrate any effect of EDTA chelation treatment in intermittent claudication.     

Nicergoline in mild to moderate dementia. A multicenter, double-blind, placebo-controlled study

In view of some controversies still existing about the real efficacy of ergot derivatives in the management of dementia, a double-blind, randomized, parallel group trial extending up to 6 months was carried out to compare the effects of nicergoline, 60 mg daily, and placebo in 315 patients suffering from mild to moderate dementia. Clinical evaluation was performed by the SCAG scale. The trial, which included a 1-month placebo run-in period, showed that both placebo and nicergoline were associated with some degree of improvement. The effect of nicergoline, however, was significantly greater and more sustained, steadily increasing with time. In particular, the difference between nicergoline and placebo in mean total SCAG score was 5.5 at 3 months (95% confidence interval: 3.6-7.4) and increased to 9.8 at 6 months (95% confidence interval: 7.8-11.8). A comparison of nicergoline versus placebo in the frequencies of changes in each item of the SCAG showed also a significant difference at 6 months, the percent of patients displaying an improvement by at least 2 points ranging from 13.5 (bothersome) to 30.2 (disorientation) in nicergoline group, against 4.1 (self-care) to 14.3 (fatigue) in placebo group. The safety of nicergoline, as judged by hemodynamic changes and drug-related adverse reactions, was quite satisfactory.