Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy.

BACKGROUND: Biosimilars of filgrastim are in widespread clinical use in Europe. This phase III study compares biosimilar filgrastim (EP2006), with the US-licensed reference product, Neupogen(®), in breast cancer patients receiving (neo)adjuvant myelosuppressive chemotherapy (TAC). PATIENTS AND METHODS: A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomized 1:1:1:1 into four arms. Two arms received only one product (nonalternating), biosimilar or reference, and two arms (alternating) received alternating treatments during each cycle (biosimilar then reference or vice versa). The primary end point was duration of severe neutropenia (DSN) during cycle 1. RESULTS: The baseline characteristics were balanced between the four treatment arms. Noninferiority of biosimilar versus the reference was demonstrated: DSN (days) in cycle 1 was 1.17 ± 1.11 (biosimilar, N = 101) and 1.20 ± 1.02 (reference, N = 103), 97.5% confidence interval lower boundary for the difference was -0.26 days (above the predefined limit of -1 day). No clinically meaningful differences were observed regarding any other efficacy parameter: incidence of febrile neutropenia (FN); hospitalization due to FN; incidence of infections; depth and time of absolute neutrophil count (ANC) nadir and time to ANC recovery during cycle 1 and across all cycles. The pattern and frequency of adverse events were similar across all treatments. CONCLUSION: This study demonstrates that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment. STUDY NUMBER: NCT01519700.

Long-term efficacy and safety of etanercept after readministration in patients with active ankylosing spondylitis.

OBJECTIVES: Treatment of ankylosing spondylitis (AS) with the tumour necrosis factor alpha (TNF-alpha) receptor fusion protein etanercept has shown efficacy in patients with active disease in randomized controlled trials (RCTs) for limited periods. The objective of the study was to assess the long-term efficacy and safety of etanercept over 1 yr, including discontinuation and readministration. METHODS: In this 54-week open observational study, 26 AS patients received 25 mg etanercept subcutaneously twice weekly after several months of discontinuation following a 6-month RCT with the same agent. All patients who developed high disease activity after cessation of etanercept, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > or = 4 and pain > or = 4 on a numerical rating scale, entered the study. Standard assessment tools, such as the Bath Ankylosing Spondylitis functional index (BASFI), were used. An intention-to-treat (ITT) and a completer analysis were performed. The results were compared with the baseline values of the open study. RESULTS: Out of the initial 30 patients, 26 (87%) were eligible for the open extension study after a mean of about 27 weeks. At week 54, 23/26 patients (88%) were still on treatment with etanercept. The ITT analysis showed that 58% (95% confidence interval 39-74%) of the patients achieved a 50% improvement of BASDAI at week 54. According to the Assessments in Ankylosing Spondylitis working group criteria, 8/26 patients (31%) were in partial remission at week 54. Function, metrology and quality of life improved significantly. Only one patient had a serious adverse event that resulted in discontinuation. CONCLUSIONS: This study shows that treatment with etanercept is efficacious and safe after readministration over 1 yr in patients with active AS not taking DMARDs or steroids.

Silica dust and lung cancer in the German stone, quarrying, and ceramics industries: results of a case-control study.

BACKGROUND: A work force based case-control study of lung cancer was performed in non-silicotic subjects exposed to crystalline silica to investigate the association between silica dust and lung cancer excluding the influence of silicosis. METHODS: Two hundred and forty seven patients with lung cancer and 795 control subjects were enrolled, all of whom had been employed in the German stone, quarrying, or ceramics industries. Smoking was used as a matching criterion. Exposure to silica was quantified by measurements, if available, or otherwise by industrial hygienists. Several indices (peak, average and cumulative exposure) were used to analyse the relationship between the level of exposure and risk of lung cancer as odds ratios (OR). RESULTS: The risk of lung cancer is associated with the year of and age at first exposure to silica, duration of exposure, and latency. All odds ratios were adjusted for these factors. Considering the peak exposure, the OR for workers exposed to high levels (>/=0.15 mg/m3 respirable silica dust which is the current occupational threshold value for Germany) compared with those exposed to low levels (<0.15 mg/m3) was 0.85 (95% CI 0.58 to 1. 25). For the time weighted average exposure the OR was 0.91 (95% CI 0.57 to 1.46). The OR for the cumulative exposure was 1.02 (95% CI 0. 67 to 1.55). No increase in risk was evident with increasing exposure. CONCLUSIONS: This study shows no association between exposure to crystalline silica and lung cancer. The exclusion of subjects with silicosis may have led to dilution with respect to the level of exposure and therefore reduced the power to detect a small risk. Alternatively, the risk of getting lung cancer may be restricted to subjects with silicosis and is not directly linked to silica dust.

[Recommendations for the study of drug combination therapy for the treatment of AIDS and cancer. Round Table No 7 at Giens XIII]. / Recommandations pour l'étude des associations de plusieurs médicaments dans les cas du traitement du SIDA et des cancers. Table Ronde No 7 de Giens XIII.

Medicine combinations for AIDS and cancer treatment are becoming common practice in most clinical stages. These combinations are based on clinical developments which do not follow established guidelines such as those for fixed combinations. There are no current recommendations which can guide these developments and we have tried to identify the critical steps. The main difficulty is to balance the fast development required by the poor prognosis of these diseases and the protection of patients who can only be subjected to combinations for which reasonable expectation of a favourable therapeutic index is foreseen. For each pathology, the pre-clinical evidence-needed before pilot clinical studies and the surrogate clinical end-points are considered (viral load for AIDS and response rate for cancer). These are prerequisities for randomized clinical trials, which are the only means of definitive assessment of new combinations versus existing therapies.

Determination of the optimal dosage regimen of captopril + hydrochlorothiazide in the treatment of moderate arterial hypertension.

A multicentre controlled trial was carried out to determine the optimal dosage of a 2/1 combination of captopril plus hydrochlorothiazide (HCTZ) in mild hypertension at three doses against placebo in a 6 week double-blind trial. The number of patients was 111:27 received placebo; 26 were treated with captopril 25 mg plus HCTZ 12.5 mg (25/12.5); 25 with captopril 50 mg plus HCTZ 25 mg (50/25); and 33 with captopril 100 mg plus HCTZ 50 mg (100/50). A significant fall in blood pressure was seen in all four groups, but was greater with the active treatments. The percentage of patients who were normalized [diastolic blood pressure (DBP) less than or equal to 90 mm Hg] or good responders (10% fall in DBP) increased as a function of the dose. At Day 21, the antihypertensive effect of 50/25 was similar to that of 100/50, but greater than that of captopril 25-HCTZ 12.5. At Day 42, the antihypertensive effects of the three doses were similar. Tolerance data showed a higher incidence of side-effects with 100/50 than with the other dosages. Thus, 50/25 appeared to be the optimal dosage for the control of mild hypertension.

Comparative study of the efficacy and tolerance of capozide and moduretic administered in a single daily dose for the treatment of chronic moderate arterial hypertension.

A comparative study was made of the effects of a new therapeutic agent consisting of 50 mg captopril and 25 mg hydrochlorothiazide (Capozide) with an already existing agent Moduretic (50 mg hydrochlorothiazide and 5 mg amiloride). In the Capozide group (32 patients), 20 achieved normal blood pressure, 8 responded but were not brought under control, and 3 were non-responders. In the Moduretic group (31 patients), 17 achieved normal blood pressure, 10 were partially controlled and 4 were non-responders. Moduretic appeared to be most effective in patients previously untreated or who had been taking only one drug, while Capozide controlled patients who had been taking 1 or 2 antihypertensive drugs which had been either ineffective or poorly tolerated. The long-acting effect of a single dose of Capozide was demonstrated by blood pressure measurements taken at least 10 hours later. Both drugs were generally well tolerated and no significant changes were observed in the laboratory measurements. The combination of an angiotensin converting enzyme inhibitor with a diuretic proved more effective than single agents in lowering raised blood pressure. We therefore conclude that Capozide is an effective alternative to traditional medication in the treatment of moderate hypertension.

[Captopril-induced eruptions: occurrence over a 3-year period]. / Toxidermies au Captopril: incidence au cours d'un traitement de 1.321 mois/patients.

With an informatized sample of 123 patients taking Captopril and treated for a total duration of 1,321 month/patients, the frequency of the dermatological symptoms induced by the drug is related. Pruritus is found in 10,5 p. 100 and rashes in 2,4 p. 100 of cases. The results are compared with those of preceeding reports, although some authors have found a higher percentage because of highin doses of the drug. The clinical features of the rashes and the proposed mechanisms are also reported.