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PubMedDate not supplied

[Methodological analysis of phase IV clinical trials performed in hospital based on the Huriet Law ].

Since the implementation of the 'Huriet law', drugs in phase IV clinical trials are handled by the pharmaceutical Department of the 'Hôpital Neuro-Cardiologique' (Lyon, France). The methodology of these trials is assessed by using a special assessment grid which enables a score for each protocol, with a maximal score of 20 and a minimal one of minus 20. Although many limitations could be advanced, results of this study show that, among 39 assessed trials, 13 trials had weak methodology (score < or = 0), 16 are middle-quality trials (score between 0 and 10) whereas 10 trials only can be considered as having a strong methodology (score > 10). So, a fairly large number of the organized phase IV trials have debatable quality. Moreover, their objective is questionable, that is essentially promotional, in spite of the 'Huriet law' and Persons Protection Committees.

Clinical Trials, Phase IV as Topic↗
PubMedDate not supplied

THE LESSA (Lebanese Short-term Study with Amisulpride) STUDY a Phase IV clinical trial in acutely ill schizophrenic patients.

BACKGROUND: Conventional antipsychotics have relatively moderate efficacy against schizophrenic negative symptoms and are associated with significant adverse events. OBJECTIVES: To assess the clinical safety and efficacy of Solian (amisulpride), an atypical antipsychotic agent of the benzamide family. PATIENTS AND METHODS: This is an 8-week cohort study including adults with schizophrenia. Daily dose was between 400 and 800 mg. Safety was measured as the cumulative risk of adverse events and efficacy as the physician's global assessment of global improvement on an ordinal scale from 0 to 6. An efficacy index, a composite measure of both safety and efficacy, was also measured on an ordinal scale from 16 the worst to 1 the best. RESULTS: Fifty-seven patients were included. Eight patients (14%) experienced at least one adverse event during the trial, mainly extra-pyramidal symptoms (EPS). None required treatment discontinuation and none was qualified as serious. Four required corrective treatment and six resolved during the 8-week follow-up. On the Global Improvement scale 31.6% of patients were "very much" or "much improved" on D14 and 81.8% on D56. 25.5% of subjects achieved complete remission over the study period. Improvement reflected also on the efficacy index, decreasing from 8.2 (SD : 3.1) on D14 to 3.4 (SD: 2.9) on D56. CONCLUSION: Amisulpride, in addition to its well-established efficacy in schizophrenic patients, offers a particularly good safety profile.

Administration, Oral↗
PubMed2006

Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow up.

BACKGROUND: Actinic keratoses (AKs) are the most common epithelial precancerous lesions, especially among individuals with light complexions. AKs are believed to progress to in situ squamous cell carcinoma (SCC) and potentially, to invasive SCC. AKs and invasive SCCs share certain histopathological features and both share genetic tumour markers and p53 mutations. Given these facts, the treatment and management of AKs are integral components to quality dermatological health care. OBJECTIVES: Topical aminolaevulinic acid-based photodynamic therapy (ALA-PDT) has been extensively studied over the last several years. This study seeks to characterize further the efficacy and safety of ALA-PDT by extending previous work to: (i) assess the long-term recurrence rate of AKs that have resolved after ALA-PDT; (ii) to characterize the histopathology of treated AK lesions that do not completely respond to ALA-PDT or recur in long-term follow up; (iii) to characterize the histopathology of untreated clinically diagnosed AK lesions in the study population at baseline; and (iv) to evaluate ALA-PDT in darker skin types than previously studied. METHODS: Patients enrolled in this study had six to 12 discrete AK lesions, either on the face or the scalp. Individual AK lesions designated for treatment were graded as either grade 1 (lesions slightly palpable and more easily felt than seen) or grade 2 (moderately thick AKs, easily seen and felt). Patients with grade 3 (very thick and/or hyperkeratotic) lesions were excluded. For each subject, two lesions at baseline were randomized to biopsy, and were not followed as part of the study while the remaining lesions (target lesions) were treated with ALA-PDT (baseline and month 2, if required) and followed for 12 months. RESULTS: Of the 110 patients enrolled, 101 completed the study. The target AK lesions in the per-protocol population clearing completely in the first and second months following a single ALA-PDT treatment (baseline) were 76% and 72%, respectively. Sixty per cent of the patients received a second ALA-PDT treatment, limited to the target AKs still present at month 2. The percentage of treated target lesions that cleared completely peaked at 86% at month 4 then decreased gradually over time to 78% at month 12. The overall recurrence rate for all lesions that were noted to be cleared at some visit during the 12-month period was 24% (162/688). Of the 162 recurrent lesions 16 were lost to follow up, seven spontaneously cleared and 139 were biopsied. With respect to the lesions biopsied, 91% (127/139) were diagnosed histopathologically as AK, with the balance of lesions being SCC (nine of 139: 7%), basal cell carcinoma (one of 139: 0.7%) and other non-AK diagnoses (two of 139: 1%). The recurrence rate for histologically confirmed AKs was 19%. The clinical diagnosis of AK by investigators appeared to be accurate, with 91% (200/220) of the untreated clinically diagnosed AK lesions being histopathologically confirmed to be AK (AK, 142/220: 65%; advanced AK, 29/220: 13%; macular AK, 29/220: 13%). Despite concentrated efforts to recruit patients with Fitzpatrick skin types IV-VI, the distribution was as follows: I, 11%; II, 36%; III, 41%; IV, 11%; V, 2%. The demographics of this study population are typical of a patient population with AK. CONCLUSIONS: ALA-PDT was shown to be an effective and safe therapy for the treatment of AKs of the face and scalp in skin types I-V, with an acceptable rate of recurrence over 12 months of histologically confirmed AKs of 19%. Phototoxicity reactions were all expected, nonserious and had essentially resolved after 1 month post-treatment independent of skin type.

Administration, Topical↗
PubMed2004

Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens.

BACKGROUND: Parenteral iron replacement and maintenance are frequently required in hemodialysis patients. However, serious adverse events have been reported after single doses of some intravenous iron products. This multicenter phase IV clinical trial examined the safety of iron sucrose for the treatment of iron deficiency and for the maintenance of iron sufficiency in hemodialysis patients. METHODS: In this safety study, iron sucrose was given in two dosing regimens. Iron deficient patients were treated with intravenous iron sucrose, 100 mg, during 10 consecutive hemodialysis sessions (replacement regimen). Iron replete patients were given iron sucrose, 100 mg intravenous (iv) over 5 minutes, weekly for 10 weeks (maintenance regimen). At the end of each 10-dose cycle, iron status was reassessed, and dosing during the subsequent cycle was based on the adequacy of iron stores as per Dialysis Outcome Quality Initiative (K/DOQI) Guidelines. With each dosing regimen, adverse events, if any, were recorded and described. RESULTS: Six hundred and sixty-five hemodialysis patients, including 80 who had experienced previous intolerance to other parenteral iron preparations, received a total of 8583 doses of iron sucrose. One hundred eighty-eight patients received more than one iv iron cycle (replacement, maintenance, or both). There were no serious or life-threatening drug-related adverse events. CONCLUSION: Iron sucrose is safe when given as treatment for iron deficiency or for maintenance of iron stores.

Adult↗
PubMed2004

Alleviation of the climacteric symptoms with oral sequential hormone replacement therapy.

The efficacy of the oral hormone replacement therapy (HRT) preparation estradiol valerate/levonorgestrel (EV/LNG, Klimonorm) in the alleviation of the menopausal complaints of peri- and postmenopausal Thai women was studied in a prospective, open, uncontrolled phase IV clinical trial. Of the 50 peri- or postmenopausal women screened, 39 completed the study. From them 31 were postmenopausal and 8 perimenopausal. The participants received EV/LNG over a period of 6 cycles. The Menopause Rating Scale II (MRS II) was used to assess the effect of EV/LNG on the menopausal symptoms. The changes in the main parameters of the MRS II during the treatment with EV/LNG showed that the general score decreased by 34.9 per cent after 3 months and was kept at the same value after 6 months of treatment. The somato-vegetative complaints decreased by 32.5 per cent after 3 months and by 35 per cent after 6 months. The psychological complaints decreased by 34.1 per cent after 3 months and by 32.9 per cent after 6 months. The urogenital complaints decreased by 29.3 per cent after 3 months, and remained at the same level after 6 months of treatment. In conclusion, the 6-months administration of the oral HRT preparation estradiol valerate/levonorgestrel caused a considerable alleviation of the climacteric symptoms in menopausal women.

Climacteric↗
PubMed2004

Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression.

Sertraline and paroxetine are frequently prescribed SSRIs for long-term treatment of major depression. Nevertheless, continuous follow-ups of drug concentrations prevailing in patients during the whole treatment period are not available. Hence, in a large phase IV clinical trial, a total of 353 patients with major depression were enrolled for a 6-month comparison of sertraline (50-150 mg daily) and paroxetine (20-60 mg daily). The present study reports the pharmacokinetic results of up to eight serum samples per patient. 1. A profound variability was found in the interindividual steady state and trough serum levels of sertraline, desmethylsertraline and paroxetine: the coefficient of variation (CV) was 59% for sertraline, 51% for desmethylsertraline, 27% for the ratio desmethylsertraline/sertraline (50 mg/day), and 71% for paroxetine (20 mg/day). The intraindividual CV for the ratio desmethylsertraline/sertraline was only 19%, indicating intraindividual metabolizing stability over time. Both sertraline and paroxetine displayed sex differences in the dose-concentration correlation. 2. It was possible to predict sertraline, but not paroxetine, steady state levels. 3. The terminal elimination t(1/2) for both drugs after 6 months of treatments was similar to data previously reported from short-term withdrawal studies. 4. No correlation between serum drug concentrations and clinical effect was detected for either sertraline or paroxetine. For the future, continuous efforts are warranted to perform PK investigations in the natural clinical setting in which the drugs are usually prescribed.

Adolescent↗
PubMed1993

Effects on recovery when isoflurane is used to supplement propofol-nitrous oxide anesthesia.

During propofol-nitrous oxide (N2O) anesthesia, volatile anesthetics are frequently administered to treat signs of inadequate anesthesia and to decrease the possibility of intraoperative awareness. Because the clinical effects of this combination have not been examined rigorously, we used data from the 1989-90 Phase IV clinical trial with propofol to evaluate recovery from propofol-N2O anesthesia with and without supplementation with isoflurane. In this study involving 15,806 patients at 1722 institutions, propofol was administered for induction and maintenance of anesthesia with N2O for procedures lasting less than 60 min. At the discretion of the anesthesiologist, volatile anesthetics were administered as needed during maintenance of anesthesia (the incidence of use of inhaled anesthetics was 14.7% for isoflurane, 2.2% for enflurane, and 0.2% for halothane). Other intraoperative medications included opioid analgesics, muscle relaxants, and anticholinergic drugs. The present study concerns the subset of 7796 patients given propofol-N2O maintenance anesthesia (intermittent bolus or continuous infusion) with or without isoflurane supplementation for procedures lasting less than 60 min. Isoflurane was used more frequently for procedures lasting 30-60 min than for those less than 30 min. Nevertheless, the maintenance dose of propofol was significantly (P < 0.05) less with isoflurane (178 vs 235 mg). Adjunctive use of isoflurane prolonged the time to awakening and to becoming oriented, but discharge times were similar for the two groups. The incidence of postoperative nausea, vomiting, recall, and excitement did not differ between the two groups. We conclude that the addition of isoflurane to a propofol-N2O anesthetic does not alter recovery from anesthesia.

Adolescent↗
PubMed2000

Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with haemophilia.

Individuals with Haemophilia are at risk from hepatitis A virus (HAV) infection through exposure to blood products. Havrix(R), an intramuscular hepatitis A vaccine, is currently recommended for the prevention of disease caused by hepatitis A virus. Because bleeding may complicate intramuscular injections in those with bleeding disorders, we conducted a randomized, Phase IV clinical trial to compare the safety and immunogenicity of Havrix(R) given by the subcutaneous (s.c) vs. intramuscular (i.m.) route. A total of 45 children with Haemophilia were vaccinated subcutaneously, while their 41 nonhaemophlic siblings were vaccinated intramuscularly, at a dose of 720 Elisa units (EL.U.) at time 0 and 6 months. All children were anti-HAV and anti-HIV negative at baseline, and the haemophilic group did not differ from their siblings in alanine aminotransferase (ALT; 25 IU L-1 vs. 22 IU L-1), or in age; 8.5 years vs. 8.7 years. The vaccine was well tolerated, with minor adverse events being similar between groups; 21 (47%) vs. 24 (58%), P > 0.05. Local symptoms included soreness in 39 (45%), erythema in 25 (29%), swelling in 21 (24%), and bruising in six (7%), with no differences between groups. The proportion seroconverting to anti-HAV IgG positive did not differ between groups; 98% vs. 97% at month 1; 82% vs. 93% at month 6; and 100% vs. 100% at month 8, respectively. The HAV geometric mean titre was lower in those with Haemophilia, 185 vs. 233 mIU mL-1 at month 1; 68 vs. 94 mIU mL-1 at month 6; and 584 vs. 1082 mIU mL-1 at month 8, respectively. We conclude that Havrix(R) is safe and immunogenic when administered s. c. in children with Haemophilia.

Adolescent↗
PubMed2005

Evaluation of a lipidocolloid wound dressing in the local management of leg ulcers.

OBJECTIVE: To evaluate the efficacy, tolerance and acceptability of Urgotul and DuoDERM E dressings in the local management of venous or mixed-aetiology leg ulcers. METHOD: This was a prospective multicentre randomised phase IV clinical trial conducted open-label in parallel groups. It involved 20 investigating centres, including hospital dermatology and vascular medicine departments, and private practices. Dermatologists and angiologists/phlebologists took part. Subjects were adult, non-immunosuppressed patients presenting with a non-infected, non-malignant leg ulcer of predominantly venous origin (ABPI > 0.8). Ulcers were between 4cm2 and 40cm2 in size, with granulation tissue covering more than 50% of their surface area. Ulcer duration ranged from three to 18 months. Patients were followed-up by the investigating physician for eight weeks on a weekly basis; this included clinical examination, wound area tracings and photographs. Nurses (hospital or visiting) assessed exudate volume and clinical appearance at dressing changes. RESULTS: Ninety-one patients were included: 47 in the Urgotul group and 44 in the DuoDERM E group. Baseline patient demographic data and wound characteristics were comparable in the two groups. After eight weeks of treatment wound surface area had reduced by a mean of 61.3% in the Urgotul group and 52.1% in the DuoDERM E group (NS); dressings were changed more frequently in the DuoDERM E group (2.54 +/- 0.57 times per week versus 2.31 +/- 0.45 in the Urgotul group, p = 0.047). Thirty-three local adverse events were recorded in 27 patients: 10 in the Urgotul group and 23 in the DuoDERM E group (p = 0.039). Nurses reported better acceptability for the Urgotul dressing, based on pain on removal, maceration and odour (p < 0.0001). CONCLUSION: Both dressings showed similar efficacy for the local treatment of venous leg ulcers. Nevertheless, medical and nursing staff reported better tolerance and acceptability for the Urgotul dressing.

Adult↗
PubMedDate not supplied

PROTECT interim results: a large multicenter study of patients with type II diabetes. Precose Resolution of Optimal Titration to Enhance Current Therapies.

The Precose Resolution of Optimal Titration to Enhance Current Therapies (PROTECT) study is an ongoing Phase IV clinical trial designed to assess the effectiveness, tolerability, and safety of acarbose tablets in patients with type II diabetes when the dosage is slowly titrated upward. This multicenter, open-label, 28-week trial will enroll approximately 7,000 type II diabetic patients. The present report describes the interim results for 2,139 patients who completed the trial as of November 1, 1996. Patients with type II diabetes enrolled in the study were inadequately controlled either with diet alone or with a sulfonylurea. The dosage of acarbose was titrated from 25 mg three times a day (TID) to 100 mg TID based on tolerability and efficacy. Efficacy of glycemic control was assessed by changes in glycated hemoglobin A1c (Hb A1c) and 1-hour postprandial plasma glucose (PPG) levels. Tolerability and safety were determined by patient reports of treatment-emergent adverse events and by review of laboratory tests. The PROTECT study confirms the previously demonstrated efficacy and safety of acarbose in improving glycemic control in patients with type II diabetes regardless of a patient's age, body weight, ethnic background, time since diagnosis, or severity of disease. mean 1-hour PPG levels declined throughout the entire treatment period, with a mean decrease from baseline of -47 mg/dL at the end of treatment. Hb A1c, the most reliable indicator of long-term glycemic control, decreased over the course of treatment, resulting in a mean decrease of -0.7% (P < 0.001). Although all patient types enrolled in the study responded positively to therapy, certain subgroups responded particularly well, such as those patients diagnosed with the disease less than 1 year ago, those treated with acarbose as monotherapy, and those with higher baseline Hb A1c levels. Adverse events were experienced by 36% of all patients and consisted primarily of gastrointestinal disturbances (flatulence, diarrhea, abdominal pain). Moderate renal insufficiency (serum creatinine levels between 1.5 and 2 mg/dL) was present in 259 patients, and no patients developed serum hepatic transaminase levels more than twice the normal range.

Acarbose↗
PubMed2001

Pharmacoeconomic assessment of propofol 2% used for prolonged sedation.

OBJECTIVE: To demonstrate that the use of propofol 2% is comparable to propofol 1% in effectiveness and in the wake-up time used for prolonged sedation. DESIGN: Open-label, case cohort study with a cohort of historical controls, phase IV clinical trial. SETTING: Medical and surgical intensive care unit (ICU) in a community hospital. PATIENTS: Fifty-one consecutive patients (medical, surgical, and trauma) admitted to our ICU requiring mechanical ventilation for >24 hrs. METHODS: All patients received propofol 2% (1-6 mg.kg-1.hr-1, starting with the lowest dose) and morphine chloride (0.5 mg.kg-1.24 hrs-1). A 4-5 level of sedation (Ramsay scale) was recommended. When weaning was indicated clinically, sedation and analgesia were interrupted abruptly, mechanical ventilation was discontinued, and the patient was connected to a T-bridge. OUTCOME MEASUREMENTS: Inability to attain the desired level of sedation with the highest dose rate of proposal, and hypertriglyceridemia >500 mg/dL, were considered therapeutic failure. The time between discontinuation of mechanical ventilation and extubation was measured. Those variables, as well as different items related to ICU cost, were compared between the study group and two historical groups sedated with propofol 1% and midazolam. RESULTS: The duration of sedation was 122.4 +/- 89.2 (sd) hrs for the propofol 2% group. The frequency of hypertriglyceridemia was 3.9% and 20.4% for the propofol 2% and the propofol 1% groups, respectively (p =.016). Therapeutic failure rates were 19.6% and 33.4% for the propofol 2% and propofol 1% groups, respectively (p =.127). The lower frequency of hypertriglyceridemia was associated with a higher number of patients reaching weaning. Weaning time was similar in the two propofol groups, 32.3 hrs ($1,744) for the propofol 2% group vs. 97.9 hrs ($5,287) for the midazolam group. Cost of sedation was $2.68 per hour for the midazolam group and $7.69 per hour for the propofol group. There was a favorable cost-benefit ratio for the propofol group, attributable to the shorter weaning time, although benefit was less than expected because higher doses of propofol 2% than propofol 1% were required during the first 48 hrs (p <.05). CONCLUSIONS: The new propofol 2% preparation is an effective sedative agent and is safe because of the low frequency of associated hypertriglyceridemia. The shorter weaning time associated with the use of propofol 2% as compared with midazolam compensates for its elevated cost. The economic benefit of propofol 2% is less than expected because higher doses of propofol 2% than propofol 1% are required over the first 48 hrs.

Aged↗
PubMed2000

[Sense and nonsense in post-authorization surveillance].

Post-authorization surveillance studies analyze the intended use of medications in accordance with their authorized labeling. They are characterized by the principle of non-intervention, i.e. they do not take influence on the decision whether or how to treat and to survey treatment in the individual patient. These aspects define the difference between surveillance studies and phase-IV clinical trials. In consequence, surveillance studies--in contrast to phase-IV trials--are not subject to the regulations of sections 40, 41 of the German Drug Law and national and international Recommendations on Good Clinical Practice (GCP). In essence, they are pharmaco-epidemiological investigations that make use of personified patient data. Within the context of the European regulatory policies they are part of the overall pharmacovigilance effort. In Germany, surveillance studies may have an additional regulatory impact. Indeed, they may be accepted as a relevant extension to the documentation on both safety and efficacy and in some cases even as an alternative to the tedious experimental investigation thereof, provided they meet newly defined quality criteria (that are discussed here more extensively). Although not developed to this purpose and although these recommendations are mainly formal with some relevant shortcomings in defining content quality, they are an important source of reference for the individual physician to guide his decision about the value and acceptability of any surveillance study, including those not primarily intended to be used in a regulatory context.

Clinical Trials, Phase IV as Topic↗
PubMed1993

[Citalopram in depression (results of an open multicenter study in phase IV of the clinical trial)].

249 depressed patients were treated by 35 psychiatrists in an open multicenter trial during 6 weeks with citalopram. The protocol enabled that naturalistic treatment conditions could be kept. The results were rated with the help of the Clinical Global Impression (CGI) scale. The treatment was successful in 77% of the patients. 5 patients dropped out because of adverse effects, 8 patients did not finish the trial due to insufficient efficacy. In 160 patients (64.2%) no adverse effects were registered. Transient mild headaches in 8.4% and nausea in 4% were the most frequent adverse events. The best effects were observed in patients who were rated as moderately ill (82.8% ameliorated) at pretreatment. Nevertheless, also 66.7% of those rated as severely ill before the treatment improved substantially. In patients treated with higher doses than 20 mg/day, the improvement rate was not higher than in those treated with 20 mg daily.

Adult↗