Terminating clinical trials without sufficient subjects.

Medical research involving human subjects can be risky and burdensome. Therefore, such research must be reviewed and approved by a Research Ethics Committee (REC). To guarantee the safety of the subjects, it is very important that these studies be conducted in accordance with the approved protocol. An important issue in this respect is whether studies include the requisite number of subjects based on the research question. The research question is unlikely to be answered reliably if the requisite number of subjects is not met. In such cases, subjects are exposed to unnecessary risks and burdens. In this descriptive study, the authors evaluated how frequently studies are completed with the required number of subjects. Moreover, the authors identified the characteristics of research that does and does not include the required number of subjects. The results of this study show that a considerable proportion of studies (41/107) were terminated although they failed to recruit a sufficient number of subjects. Furthermore, the authors found that investigator-initiated studies have significantly (p=0.028) more problems in recruiting the requisite number of subjects than studies initiated by pharmaceutical companies. Potential solutions are discussed to reduce the number of studies that do not include a sufficient number of subjects.

The long-term outcome of transcutaneous electrical nerve stimulation in the treatment for patients with chronic pain: a randomized, placebo-controlled trial.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is an easy to use analgesic intervention. However, long-term randomized placebo-controlled studies with treatment periods of more than 3 months have not been executed to date. The aim of our study is to explore the long-term (1 year) time course of the treatment effects of TENS compared to placebo (sham TENS). METHOD: We performed a randomized placebo-controlled trial in patients with chronic pain (165), referred to a multidisciplinary pain center of a university hospital. Main outcome measures are the proportion of patients satisfied with treatment result and willing to continue treatment, pain intensity, pain disability, and perceived health status. RESULTS: Survival analysis of time courses of proportions of satisfied patients revealed no significant differences (P = 0.79; log-rank test) for TENS treatment compared to sham TENS. After 1 year, 30% (24/81) of the patients of the TENS group and 23% (19/82) of the sham TENS group were satisfied with treatment result. These patients experienced a mean overall improvement of 62.7% (n = 43). This effect was not significantly different between both groups. For satisfied patients, there were no differences in pain intensity or disability and perceived health status between the TENS and sham TENS group. CONCLUSIONS: Transcutaneous electrical nerve stimulation and sham TENS show similar effects in patients with chronic pain over a period of 1 year. We found support for a long sustained placebo effect.

Validation of clinical and image skin scoring systems for a single chronic discoid lupus erythematosus lesion.

OBJECTIVE: The purpose of this study was to achieve a validated clinical and image scoring system for a single chronic discoid lupus erythematosus (CDLE) lesion. METHODS: Fifteen patients with a CDLE lesion were scored twice by four observers and clinical photographs were taken. These pictures were assessed by the same four observers at two time points. Patients were scored using the DLE-Skin Score (DLE-SS). In addition, the DLE-Photo Score (DLE-PS) was calculated. Statistical analysis was carried out by measuring inter- and intra-observer agreement for both methods and by measuring the correlation between the DLE-SS and DLE-PS. RESULTS: Both the DLE-SS and DLE-PS proved reliable methods in the assessment of CDLE. The inter-observer variability of the DLE-SS and DLE-SS was low. The intra-observer variability was estimated to be 0 in both methods. The correlation coefficient between the DLE-SS and DLE-PS was high (0.81). CONCLUSION: Both the DLE-SS and the DLE-PS are reliable and easy-to-use methods to score disease activity in CDLE patients, and can be used in monitoring single target lesions in clinical trials.

Predicting outcome of TENS in chronic pain: a prospective, randomized, placebo controlled trial.

UNLABELLED: Transcutaneous electrical nerve stimulation (TENS) is an easy to use non-invasive analgesic intervention applied for diverse pain states. However, effects in man are still inconclusive, especially for chronic pain. Therefore, to explore the factors predicting result of TENS treatment in chronic pain we conducted a prospective, randomized, placebo-controlled trial (n=163), comparing high frequency TENS (n=81) with sham TENS (n=82). Patients' satisfaction (willingness to continue treatment; yes or no) and pain intensity (VAS) were used as outcome measures. The origin of pain and cognitive coping strategies were evaluated as possible predictors for result of TENS treatment. RESULTS: Fifty-eight percent of the patients in the TENS group and 42.7% of the sham-TENS group were satisfied with treatment result (chi square=3.8, p=0.05). No differences were found for pain intensity. Patients diagnosed with osteoarthritis and related disorders (especially of the vertebral column) or peripheral neuropathic pain were less satisfied with high frequency TENS (OR=0.12 (95% CI 0.04-0.43) and 0.06 (95% CI 0.006-0.67), respectively). Injury of bone and soft tissue (especially postsurgical pain disorder) provided the best results. Treatment modality or interactions with treatment modality did not predict intensity of pain as a result of treatment. We conclude, that predicting the effect of high frequency TENS in chronic pain depends on the choice of outcome measure. Predicting patients' satisfaction with treatment result is related to the origin of pain. Predicting pain intensity reflects mechanisms of pain behavior and perceived control of pain, independent of treatment modality. Pain catastrophizing did not predict TENS treatment outcome.

Outcome of transcutaneous electrical nerve stimulation in chronic pain: short-term results of a double-blind, randomised, placebo-controlled trial.

The aim of this study was to test the efficacy of shortterm transcutaneous electrical nerve stimulation (TENS) treatment in chronic pain with respect to pain intensity and patients' satisfaction with treatment results. We therefore performed a randomised controlled trial comparing TENS and sham TENS. Patients, researchers and therapists were blinded for treatment allocation. One hundred and sixty-three patients with chronic pain referred to the Pain Centre entered the study. Conventional TENS and sham TENS were applied in the segments of pain, for a period of ten days. Outcome measures were pain intensity (visual analogue scale) and patients' satisfaction with treatment result (yes or no). The proportions of patients satisfied with treatment result differed significantly for TENS compared to sham TENS (58 and 42.7% respectively, chi(2)=3.8, p=0.05). However, no differences in pain intensity were found for patients treated with TENS or sham TENS. Only for patients satisfied with treatment results pain intensity gradually decrease equally both for TENS and sham TENS with repeated treatment application.

Cost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer.

PURPOSE: Recently, a Dutch, randomized, phase III trial demonstrated that, in small-cell lung cancer patients at risk of chemotherapy-induced febrile neutropenia (FN), the addition of granulocyte colony-stimulating factor (GCSF) to prophylactic antibiotics significantly reduced the incidence of FN in cycle 1 (24% v 10%; P = .01). We hypothesized that selecting patients at risk of FN might increase the cost-effectiveness of GCSF prophylaxis. METHODS: Economic analysis was conducted alongside the clinical trial and was focused on the health care perspective. Primary outcome was the difference in mean total costs per patient in cycle 1 between both prophylactic strategies. Cost-effectiveness was expressed as costs per percent-FN-prevented. RESULTS: For the first cycle, the mean incremental costs of adding GCSF amounted to 681 euro (95% CI, -36 to 1,397 euro) per patient. For the entire treatment period, the mean incremental costs were substantial (5,123 euro; 95% CI, 3,908 to 6,337 euro), despite a significant reduction in the incidence of FN and related savings in medical care consumption. The incremental cost-effectiveness ratio was 50 euro per percent decrease of the probability of FN (95% CI, -2 to 433 euro) in cycle 1, and the acceptability for this willingness to pay was approximately 50%. CONCLUSION: Despite the selection of patients at risk of FN, the addition of GCSF to primary antibiotic prophylaxis did not result in cost savings. If policy makers are willing to pay 240 euro for each percent gain in effect (ie, 3,360 euro for a 14% reduction in FN), the addition of GCSF can be considered cost effective.

Sulprostone reduces the need for the manual removal of the placenta in patients with retained placenta: a randomized controlled trial.

OBJECTIVE: The purpose of this study was to determine the extent that the administration of sulprostone reduces the need for manual removal of the placenta in patients with retained placenta. STUDY DESIGN: A double-blinded sequential randomized controlled trial of sulprostone versus placebo was conducted among 103 patients with retained placenta. RESULTS: In the first phase of this sequential study, sulprostone was compared with placebo. The null hypothesis of equal effectiveness of both treatments was rejected after 50 patients. In patients with retained placenta, the placenta was expelled after sulprostone in 13 of 24 cases (51.8%, bias adjusted), whereas expulsion after placebo was achieved in only 4 of 26 cases (17.6%, bias adjusted). The difference was significant (P = .034). In the second phase of the study, in which the placebo arm was stopped, results were confirmed; in 25 of 53 patients (47%), the placenta was expelled. CONCLUSION: Sulprostone reduces the need for the manual removal of the placenta by 49%.

Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a Dutch Randomized Phase III Study.

PURPOSE: Febrile neutropenia (FN) is a major complication of chemotherapy. Antibiotics as well as granulocyte colony-stimulating factor (G-CSF) are effective in preventing FN. This multicenter randomized phase III trial determines whether the addition of G-CSF to antibiotic prophylaxis can further reduce the incidence of FN in patients with small-cell lung cancer (SCLC) at the risk of FN. PATIENTS AND METHODS: Patients (N = 175) were stratified for stage of disease, performance status, age, and prior chemotherapy treatment, and were randomly assigned for treatment with cyclophosphamide, doxorubicin, and etoposide (CDE), followed by prophylactic antibiotics alone (ciprofloxacin and roxithromycin) or by antibiotics in combination with G-CSF on days 4 to 13. RESULTS: In cycle 1, 20 patients (24%) in the antibiotics group developed FN compared with nine patients (10%) in the antibiotics plus G-CSF group (P = .01). In cycles 2 to 5, the incidences of FN were practically the same in both groups (17% v 11%). Only the treatment parameters (odds ratio, 0.33; 95% CI, 0.14 to 0.78) and age (1.067 per year; 95% CI, 1.013 to 1.0124) were related to the probability of FN in cycle 1. CONCLUSION: Primary G-CSF prophylaxis added to primary antibiotic prophylaxis is effective in reducing FN and infections in SCLC patients at the risk of FN with the first cycle of CDE chemotherapy. For patients with similar risk of FN, the combined use of prophylactic antibiotics plus G-CSF can be considered, specifically in the first cycle of chemotherapy.

The effect of treatment on quality of life in psoriasis patients.

Psoriasis is a chronic skin disease with substantial impact on patients' social and relational ways of living and subsequently on their quality of life. The aim of this study was to evaluate the health-related quality of life (HRQoL) of patients with moderate to severe psoriasis treated with short contact dithranol treatment, UVB phototherapy or inpatient dithranol treatment. HRQoL was evaluated in an open randomized multicentre study by appliance of the Dutch short form of the Sickness Impact Profile and the Psoriasis Disability Index; 250 patients were included. Successful short contact dithranol treatment and UVB phototherapy both led to a comparable improvement in HRQoL immediately after treatment until the end of the follow-up (maximum 1 year). Inpatients experienced a more impaired HRQoL and showed no significant improvement in HRQoL directly following treatment. At the end of the study HRQoL became comparable for all treatment groups. All three treatments led to substantial improvement in HRQoL; however, patients treated by short contact treatment or UVB showed a better HRQoL than inpatients.

Diaphragm dysfunction in chronic obstructive pulmonary disease.

RATIONALE: Hypercapnic respiratory failure because of inspiratory muscle weakness is the most important cause of death in chronic obstructive pulmonary disease (COPD). However, the pathophysiology of failure of the diaphragm to generate force in COPD is in part unclear. OBJECTIVES: The present study investigated contractile function and myosin heavy chain content of diaphragm muscle single fibers from patients with COPD. METHODS: Skinned muscle fibers were isolated from muscle biopsies from the diaphragm of eight patients with mild to moderate COPD and five patients without COPD (mean FEV(1) % predicted, 70 and 100%, respectively). Contractile function of single fibers was assessed, and afterwards, myosin heavy chain content was determined in these fibers. In diaphragm muscle homogenates, the level of ubiquitin-protein conjugation was determined. RESULTS: Diaphragm muscle fibers from patients with COPD showed reduced force generation per cross-sectional area, and reduced myosin heavy chain content per half sarcomere. In addition, these fibers had decreased Ca2+ sensitivity of force generation, and slower cross-bridge cycling kinetics. Our observations were present in fibers expressing slow and 2A isoforms of myosin heavy chain. Ubiquitin-protein conjugation was increased in diaphragm muscle homogenates of patients with mild to moderate COPD. CONCLUSIONS: Early in the development of COPD, diaphragm fiber contractile function is impaired. Our data suggest that enhanced diaphragm protein degradation through the ubiquitin-proteasome pathway plays a role in loss of contractile protein and, consequently, failure of the diaphragm to generate force.

Minimization of sample size when comparing two small probabilities in a non-inferiority safety trial.

In clinical trials success rates of two treatments to be compared often range from 10 to 90 per cent. When the comparison probabilities are (much) smaller than 10 per cent, standard methods for sample size and power calculations may provide invalid results. This situation may occur when there is interest in safety rather than in efficacy. In such trials, no more patients should be included than strictly necessary. We compared the results of maximum likelihood methods for the computation of sample sizes in a non-inferiority trial, including exact procedures and considered unequal sample sizes for experimental and reference treatment. An exact, unequal sample size maximum likelihood procedure is advocated when the specified non-zero risk difference under the null hypothesis is not too large. Such a procedure is also indicated when the parameter of interest is the relative risk, rather than the risk difference.

Cost-effectiveness of infant orthopedic treatment regarding speech in patients with complete unilateral cleft lip and palate: a randomized three-center trial in the Netherlands (Dutchcleft).

OBJECTIVE: To investigate the cost-effectiveness of infant orthopedic treatment (IO), compared with no such treatment in children with complete unilateral cleft lip and palate (UCLP) focusing on the effects on speech development at age 2.5 years. DESIGN: In a three-center prospective, randomized clinical trial (Dutchcleft), two groups of children with complete UCLP were followed longitudinally: one group was treated with IO based on a modified Zurich approach in the first year of life (IO group) and the other group did not receive this treatment (non-IO group). PATIENTS: The participants had complete UCLP without soft tissue bands or other malformations. They were born at term and their parents were native Dutch speakers. OUTCOME MEASURES: The effect of IO on speech development at age 2.5 years was measured blindly by five expert listeners judging the "total impression of speech quality" on a 10-point equal-appearing interval scale. Costs were measured from a societal viewpoint in Euro. RESULTS AND CONCLUSION: The IO group (n = 10) obtained a statistically significant higher rating, compared with the non-IO group (n = 10). The effect size was large, indicating that the improvement may be considered a clinically important change. The cost for treatment by the orthodontist was higher in the IO group. For both groups, the mean cost was related to the mean rating for "total impression of speech quality." The resulting cost-effectiveness for IO, compared to non-IO was 1041 for 1.34 point speech quality improvement. The financial investment that is necessary to obtain this improvement seems limited. Thus, from the perspective of speech development, the cost-effectiveness of IO over non-IO seems acceptable at this point in time.

Administration of indinavir and low-dose ritonavir (800/100 mg twice daily) with food reduces nephrotoxic peak plasma levels of indinavir.

BACKGROUND: The objective of this study was to compare indinavir peak plasma (Cmax) values after administration of indinavir/ritonavir 800/100 mg on an empty stomach or with food. High indinavir Cmax values have been associated with indinavir-related nephrotoxicity. METHODS: This was an open-label, randomized, two-treatment, two-period, cross-over pharmacokinetic study performed at steady state. HIV-infected patients who had been using indinavir/ritonavir 800/100 mg twice daily for at least 4 weeks were randomized to take this combination with a light breakfast (two filled rolls and 130 ml of fluid) on a first study day, and without food on a second day, or in the reverse order. The pharmacokinetics of indinavir and ritonavir were assessed after plasma and urine sampling during 12 h. RESULTS: Data for nine patients were evaluated. Administration of indinavir/ritonavir 800/100 mg on an empty stomach resulted in a higher indinavir Cmax [geometric mean (GM) ratio - fasting/fed and 95% confidence interval (CI): 1.28 (1.08-1.52), P=0.01] and a trend to a shorter indinavir tmax (P=0.07) compared to administration with food. The mode of administration of indinavir/ritonavir did not affect plasma indinavir Cmax and AUC values, parameters that have been associated with the antiviral efficacy of indinavir, nor the urinary excretion of indinavir. CONCLUSIONS: Administration of indinavir/ritonavir 800/100 mg on an empty stomach results in a higher indinavir Cmax compared to ingestion with a light meal. Stated the other way round, intake with a light meal reduces indinavir Cmax, which probably reflects a food-induced delay in the absorption of indinavir. It is recommended to administer indinavir/ritonavir 800/100 mg with food, as a possible means to prevent indinavir-related nephrotoxicity in patients who start or continue with this regimen.

Preconception counseling improves folate status of women planning pregnancy.

OBJECTIVE: To assess whether counseling women planning pregnancy to start or continue folic acid supplementation improves folate status. METHODS: Women and their partners reported folic acid supplement intake in a preconceptional health questionnaire, and the women were categorized as reported "users" or "nonusers" of supplements before counseling. The use of periconceptional folic acid was addressed at a subsequent preconceptional consultation. Differences between reported supplement users and nonusers before counseling as well as between assumed users and nonusers of folic acid (with precounseling red cell and serum folate levels above and below 590 nmol/L and 20 nmol/L, respectively) were analyzed. RESULTS: A total of 111 (66%) of 168 eligible women participated. Estimated mean red cell folate levels of women who reported no use of folic acid supplements before counseling increased significantly after 4 months from 540 nmol/L to 680 nmol/L. Red cell folate levels of women who reported taking supplements (44%) remained stable up to 1 year after counseling. Women with low precounseling folate levels showed a highly significant mean increase in red cell folate from 475 nmol/L to 689 nmol/L 4 months after counseling. CONCLUSION: Addressing periconceptional folic acid use at a preconceptional consultation improves folate status among women planning to conceive.

The efficacy of radiofrequency lesioning of the cervical spinal dorsal root ganglion in a double blinded randomized study: no difference between 40 degrees C and 67 degrees C treatments.

The efficacy of radiofrequency lesion treatment of the cervical dorsal root ganglion (RF-DRG) in cervicobrachialgia was investigated in 61 patients by a randomized prospective double blinded study. Before lesion treatment the putative pain provoking spinal root was identified by diagnostic blocks with a local anesthetic agent. One group of patients (n = 32, group I) was treated with a radiofrequency lesion of 67 degrees C and in a control group (n = 29, group II) a temperature of 40 degrees C was applied. Three months after treatment a significant reduction in VAS scores was demonstrated in both groups. The outcome of the treatments was identical (VAS reduction: group I, 1.7; group II, 1.9; P = 0.001). In group I a VAS reduction of 3 or more occurred in 11/31 (34%) and in group II in 11/29 (38%) of patients. A VAS reduction of 2 or more occurred in group I in 15/31 (47%) and in group II in 15/29 (51%) of patients. This study suggests that treatment with 40 degrees C radiofrequency application of the dorsal root ganglion is equally effective as treatment at 67 degrees C. Further appraisal of this treatment is required.