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[Therapeutic trials in outpatients. Apropos of triazolam trials].

Clinical trials conducted in general practice are more especially interesting as they enable to test a drug in the real conditions of use. On the other hand, these trials are beneficial to the G.P. (new image, rupture of his loneliness, change in his prescription habits, contact with hospitals). The methodology, as for hospital studies, must be rigorous. As a matter of fact, these two types of studies are additional and the cooperation between the G.P.'s and the pharmaceutical industry can conduct to the solution of specific problems: drug interaction--long-term therapeutic effect--new indications. This double blind cross over study comparing triazolam and nitrazepam conducted by G.P.'s on insomniacs is the first French clinical study intended for the registration application and done according to this methodology. This work is an exemple of the new opportunity offered to G.P.'s in future. The results have shown that: on 54 patients (23 male and 31 female) of an average age: 48, 32 have preferred triazolam, 13 have preferred nitrazepam, 9 have had no preference.

Adult↗

Sion thrombolysis trial--randomised trial of intravenous thrombolysis & primary percutaneous transluminal coronary angioplasty for acute myocardial infarction [AMI]--feasibility phase data of angioplasty limb.

Reperfusion in acute myocardial Infarction [AMI] can be realised by thrombolytic therapy or percutaneous transluminal coronary angioplasty [PTCA] has theoretical advantage but hardly any randomised trials have been published till recently to compare the two modalities. We started the STAT trial with this objective. Patients of AMI were randomised to thrombolytic therapy or PTCA. In the present article we present the phase I data of the PTCA limb. The procedural success rate was 100% with no procedural mortality. In-hospital mortality was 10% [Anterior Infarction 0%, Inferior infarction 20%]. Recurrence of angina occurred in 10% patients. Direct PTCA to left anterior descending artery appeared to be more rewarding than PTCA to right coronary artery.

Adult↗

The verdict on jury trials for juveniles: the effects of defendant's age on trial outcomes.

With the progression to more adult-like policies and procedures for youth in the justice system, the right to a jury trial has been extended to young offenders. These youth would not be tried by a jury of their peers, however, but by a jury of adults. The concern is that adult jurors may hold negative attitudes about youth that might influence their decision making in a case involving a young defendant. Two studies examined whether and under what conditions defendant's age affects jurors' decisions about the guilt and sentencing of an accused. In study 1, data were gathered from two samples of jury eligible adults: one university sample and one public sample. Mock jurors read written transcripts of a trial involving a defendant who was presented as either 13, 17, or 25 years of age. Results indicated that the defendant's age had no effect on mock jurors' verdict or their ratings of defendant guilt. However, younger defendants were granted shorter sentences than the adult defendants. In study 2, mock jurors read the same trial presented in study 1 but were asked to deliberate about the case and render group verdicts. These group verdicts did not differ significantly by defendant's age. Age-related themes that emerged from group deliberations were identified, and results indicated that age tended to be used as a mitigating factor in favor of youth rather than against them. These findings are discussed in terms of their implications for youth justice policy and practice.

Adolescent↗

A multicenter phase II trial of ramucirumab plus irinotecan for early recurrence of gastric cancer during or after adjuvant chemotherapy with docetaxel plus S-1 therapy: the RAMIEL trial (OGSG1901).

BACKGROUND: There is currently no established chemotherapy regimen for early recurrence of pathological stage III gastric cancer (GC) following adjuvant chemotherapy with docetaxel plus S-1 (DS) after D2 gastrectomy. We aimed to evaluate the efficacy and safety of ramucirumab plus irinotecan in patients with GC who experienced early recurrence during or within 6 months after DS adjuvant chemotherapy. METHODS: This prospective, open-label, multicenter phase II trial enrolled eligible patients treated at 25 centers of the Osaka Gastrointestinal Cancer Chemotherapy Study Group in Japan. Patients received ramucirumab (8 mg/kg) and irinotecan (150 mg/m2) every 2 weeks. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size was set at 40 based on a threshold median OS of 7 months and an expected median OS of 11 months, with a one-sided alpha error of 0.05 and a power of 0.80. RESULTS: Between November 2019 and July 2023, 43 patients were enrolled, and 39 were included in the analysis after excluding three ineligible patients and one who did not initiate protocol treatment. The median OS was 15.9 months (95% CI: 8.8-42.0; p = 0.003). The median PFS was 5.5 months (95% CI: 3.9-8.1), and the ORR was 38.5%. Grade  ≥ 3 adverse events, including neutropenia (25.6%) and hypertension (25.6%), were observed in more than 20% of patients. CONCLUSION: Ramucirumab plus irinotecan demonstrated promising efficacy and manageable toxicity in patients with early recurrence of GC following adjuvant DS therapy. TRIAL REGISTRATION: This study was prospectively registered in the Japan Registry of Clinical Trials (jRCTs05119071, October 6, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs051190071 ).

Docetaxel↗

The role of clinical drug trial methodology with respect to studies of new drugs. Clinical trials of timolol.

The use of the Randomized Clinical Trial (RCT) to assess the safety and efficacy of a new drug or treatment can provide a clear evaluation of the relative benefits and risks of the new therapy as compared to the longer-established treatment methodology. In some cases, such as insulin, the benefits are immediately apparent; in other cases, such as photocoagulation for proliferative diabetic retinopathy, the consensus is not so easily obtained, and the clinical trial can supply the answer. Furthermore, the RCT provides the opportunity to identify adverse reactions, in particular those which present with a seemingly unrelated or unexpected set of symptoms. In conducting clinical trials of timolol, researchers must be alert for beta-adrenergic antagonist effects, such as were seen with practolol, and should be especially careful to note early, mild reactions which may be the forerunners of later, more severe or irreversible adverse effects.

Diabetic Retinopathy↗

Community trial to decrease ambulance diversion hours: the San Diego county patient destination trial.

STUDY OBJECTIVE: Emergency department (ED) ambulance diversion is a major issue in many communities. When patients do not reach requested facilities, challenges in care are compounded by lack of available medical records and delays in transferring admitted patients back to the originally requested facility. We seek to evaluate a community intervention to reduce ambulance diversion. METHODS: This was a community intervention in a county of 2.8 million individuals. Ambulance diversion guidelines were revised for all ambulance agencies and EDs. Participation by EDs was voluntary, and main outcome measures, which included ambulance transports, ambulance diversions, and bypass hours, were compared for the pretrial, trial, and posttrial periods. RESULTS: A total of 235,766 patients were transported to an ED by advanced life support ambulance during the 2-year study period. There was a significant decrease in the number of patients who did not reach the requested facility because of ambulance diversion for the trial period (n=322) and posttrial period (n=449) compared with the pretrial period (n=1,320; -998 diverted patients per month [95% confidence interval (CI) -1,162 to -833 patients] and -871 diverted patients per month [95% CI -963 to -780 patients], respectively). There was also a significant decrease in average monthly hours on diversion for the trial period (n=1,079) and posttrial period (n=1,774) compared with the pretrial period (n=4,007; -2,928 hours on bypass [95% CI -3,936 to -1,919 hours on bypass] and -2,232 hours on bypass [95% CI -3,620 to -2,235 hours on bypass], respectively). CONCLUSION: A voluntary community-wide approach to reducing hospital ED diversion and getting more ambulance patients to requested facilities was effective.

Adolescent↗

Rationale and Study Design of the GUIDANCE trial: A Multicenter Phase II Trial of Maintenance Durvalumab and Olaparib After Standard Fist Line Treatment (Carboplatin/Cisplatin, Etoposide, and Durvalumab) in HRD Positive Extensive Disease (ED) Small-cell Lung Cancer (SCLC) (AIO-TRK-0124/ass).

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. METHODS: GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. DISCUSSION: This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.

DNA-damage repair↗

The effects of note-taking and trial transcript access on mock jury decisions in a complex civil trial.

Mock juries were either permitted to take notes or not and provided with access to the trial transcript during deliberations or were not given access. Juries viewed a videotape of a complex trial involving multiple plaintiffs. Note-taking juries were able to distinguish among differentially worthy plaintiffs when assigning awards while non note takers did not distinguish among the plaintiffs and allocated higher overall compensation. Note-taking was significantly more effective than access to trial transcripts in increasing jury competence. Note-taking juries appeared better able to recognize probative evidence and reject false lures than were non note-taking juries. Limits and implications of the present study were discussed.

Adolescent↗

Juveniles' competence to stand trial: a comparison of adolescents' and adults' capacities as trial defendants.

Abilities associated with adjudicative competence were assessed among 927 adolescents in juvenile detention facilities and community settings. Adolescents' abilities were compared to those of 466 young adults in jails and in the community. Participants at 4 locations across the United States completed a standardized measure of abilities relevant for competence to stand trial (the MacArthur Competence Assessment Tool--Criminal Adjudication) as well as a new procedure for assessing psychosocial influences on legal decisions often required of defendants (MacArthur Judgment Evaluation). Youths aged 15 and younger performed more poorly than young adults, with a greater proportion manifesting a level of impairment consistent with that of persons found incompetent to stand trial. Adolescents also tended more often than young adults to make choices (e.g., about plea agreements) that reflected compliance with authority, as well as influences of psychosocial immaturity. Implications of these results for policy and practice are discussed, with an emphasis on the development of legal standards that recognize immaturity as a potential predicate of incompetence to stand trial.

Adolescent↗

Sum of Pain Intensity Differences (SPID) in migraine trials. A comment based on four rizatriptan trials.

Sum of Pain Intensity Difference (SPID) is an outcome measure that summarizes treatment response over a clinically relevant period. SPID is widely reported in clinical trials of analgesics but has been little used in migraine trials. We compared SPID over 2 h with the standard migraine outcome measures of pain-free at 2 h and headache relief at 2 h using data from four published clinical trials of rizatriptan in migraine patients. In assessing treatment response (rizatriptan and sumatriptan versus placebo, rizatriptan versus sumatriptan, within-treatment dose effects), SPID usually yielded similar results to the more easily understood pain-free measure.

Humans↗

[A rare trial eyeglass case with binocular trial lenses].

In this article the author describes a rare trial frame case in the medical history collection of the Ruhr University at Bochum. It has 24 binocular trial lenses which are similar to be early "Nuremberg wire spectacles." The lens power is expressed as the focal length, measured in Rhenish inches. Converted into diopters, the refractive power of the lenses ranges from +/- 1.0 to +/- 8.0 D.spherical. The case also contains six pairs of plane lenses tinted in various intensities of azure blue and four pairs of plane lenses tinted smoke-gray. It contains no astigmatic lenses. Since the metric system, with the diopter as a unit of refractive power, was introduced in the optical industry in 1875, it may be assumed that this case was in use before then. However, the design of the binocular trial frames suggests that they may be considerably older.

Eyeglasses↗

A maximum-likelihood estimator for trial-to-trial variations in noisy MEG/EEG data sets.

The standard procedure to determine the brain response from a multitrial evoked magnetoencephalography (MEG) or electroencephalography (EEG) data set is to average the individual trials of these data, time locked to the stimulus onset. When the brain responses vary from trial-to-trial this approach is false. In this paper, a maximum-likelihood estimator is derived for the case that the recorded data contain amplitude variations. The estimator accounts for spatially and temporally correlated background noise that is superimposed on the brain response. The model is applied to a series of 17 MEG data sets of normal subjects, obtained during median nerve stimulation. It appears that the amplitude of late component (30-120 ms) shows a systematic negative trend indicating a weakening response during stimulation time. For the early components (20-35 ms) no such a systematic effect was found. The model is furthermore applied on a MEG data set consisting of epileptic spikes of constant spatial distribution but varying polarity. For these data, the advantage of applying the model is that positive and negative spikes can be processed with a single model, thereby reducing the number of degrees of freedom and increasing the signal-to-noise ratio.

Algorithms↗

Prehension synergies: trial-to-trial variability and principle of superposition during static prehension in three dimensions.

We performed three-dimensional analysis of the conjoint changes of digit forces during prehension (prehension synergies) and tested applicability of the principle of superposition to three-dimensional tasks. Subjects performed 25 trials at statically holding a handle instrumented with six-component force/moment sensors under seven external torque conditions; -0.70, -0.47, -0.23, 0.00, 0.23, 0.47, and 0.70 Nm about a horizontal axis in the plane passing through the centers of all five digit force sensors (the grasp plane). The total weight of the system was always 10.24 N. The trial-to-trial variability of the forces produced by the thumb and the virtual finger (an imagined finger producing the same mechanical effects as all 4 finger forces and moments combined) increased in all three dimensions with the external torque magnitude. The sets of force and moment variables associated with the moment production about the vertical axis in the grasp plane and the axis orthogonal to the grasp plane consisted of two noncorrelated subsets each; one subset of variables was related to the control of grasping forces (grasp control) and the other sassociated with the control of the orientation of the hand-held object (torque control). The variables associated with the moment production about the horizontal axis in the grasp plane did not include the grip force (the normal thumb and virtual finger forces) and showed more complex noncorrelated subsets. We conclude that the principle of superposition is valid for the prehension in three dimensions. The observed high correlations among forces and moments associated with the control of object orientation could be explained by chain effects, the sequences of cause-effect relations necessitated by mechanical constraints.

Adult↗

Early and long-term outcome of elective stenting of the infarct-related artery in patients with viability in the infarct-area: Rationale and design of the Viability-guided Angioplasty after acute Myocardial Infarction-trial (The VIAMI-trial).

BACKGROUND: Although percutaneous coronary intervention (PCI) is becoming the standard therapy in ST-segment elevation myocardial infarction (STEMI), to date most patients, even in developed countries, are reperfused with intravenous thrombolysis or do not receive a reperfusion therapy at all. In the post-lysis period these patients are at high risk for recurrent ischemic events. Early identification of these patients is mandatory as this subgroup could possibly benefit from an angioplasty of the infarct-related artery.Since viability seems to be related to ischemic adverse events, we initiated a clinical trial to investigate the benefits of PCI with stenting of the infarct-related artery in patients with viability detected early after acute myocardial infarction. METHODS: The VIAMI-study is designed as a prospective, multicenter, randomized, controlled clinical trial. Patients who are hospitalized with an acute myocardial infarction and who did not have primary or rescue PCI, undergo viability testing by low-dose dobutamine echocardiography (LDDE) within 3 days of admission. Consequently, patients with demonstrated viability are randomized to an invasive or conservative strategy. In the invasive strategy patients undergo coronary angiography with the intention to perform PCI with stenting of the infarct-related coronary artery and concomitant use of abciximab. In the conservative group an ischemia-guided approach is adopted (standard optimal care).The primary end point is the composite of death from any cause, reinfarction and unstable angina during a follow-up period of three years. CONCLUSION: The primary objective of the VIAMI-trial is to demonstrate that angioplasty of the infarct-related coronary artery with stenting and concomitant use of abciximab results in a clinically important risk reduction of future cardiac events in patients with viability in the infarct-area, detected early after myocardial infarction.

Journal Article↗

A randomised controlled trial to assess the efficacy of Laparoscopic Uterosacral Nerve Ablation (LUNA) in the treatment of chronic pelvic pain: The trial protocol [ISRCTN41196151].

BACKGROUND: Chronic pelvic pain is a common condition with a major impact on health-related quality of life, work productivity and health care utilisation. The cause of the pain is not always obvious as no pathology is seen in 40-60% of the cases. In the absence of pathology there is no established treatment. The Lee-Frankenhauser sensory nerve plexuses and parasympathetic ganglia in the uterosacral ligaments carry pain from the uterus, cervix and other pelvic structures. Interruption of these nerve trunks by laparoscopic uterosacral nerve ablation (LUNA) may alleviate pain. However, the balance of benefits and risks of this intervention have not been reliably assessed. LUNA has, nevertheless, been introduced into practice, although there remains controversy regarding indications for LUNA. Hence, there is an urgent need for a randomised controlled trial to confirm, or refute, any worthwhile effectiveness. The principal hypothesis is that, in women with chronic pelvic pain in whom diagnostic laparoscopy reveals either no pathology or mild endometriosis (AFS score </= 5) LUNA alleviates pain and improves life quality at 12 months. METHODS/DESIGN: The principal objective is to test the hypothesis that in women with chronic pelvic pain in whom diagnostic laparoscopy reveals either no pathology or mild endometriosis (AFS score </= 5) LUNA alleviates pain and improves life quality at 12 months. A multi-centre, prospective, randomised-controlled-trial will be carried out with blind assessment of outcomes in eligible consenting patients randomised at diagnostic laparoscopy to LUNA (experimental group) or to no pelvic denervation (control group). Postal questionnaires including visual analogue scale for pain (primary outcome), an index of sexual satisfaction and the EuroQoL 5D-EQ instrument (secondary outcomes) will be administered at 3, 6 and 12 months. The primary assessment of the effectiveness of LUNA will be from comparison of outcomes at the one-year follow-up, although the medium-term and longer-term risks and benefits of LUNA will also be evaluated.The sample size for this trial has been estimated as 420 patients in total using the hypothesis that LUNA will alleviate pain symptoms (i.e. reduce pain scores on a VAS) more than no intervention at one-year following diagnostic laparoscopy and taking into consideration 20% loss to follow-up. The intention to treat analysis to address the principal research questions will be conducted using the one-year follow-up data.

Journal Article↗

A randomized trial to assess the impact of opinion leader endorsed evidence summaries on the use of secondary prevention strategies in patients with coronary artery disease: the ESP-CAD trial protocol [NCT00175240].

BACKGROUND: Although numerous therapies have been shown to be beneficial in the prevention of myocardial infarction and/or death in patients with coronary disease, these therapies are under-used and this gap contributes to sub-optimal patient outcomes. To increase the uptake of proven efficacious therapies in patients with coronary disease, we designed a multifaceted quality improvement intervention employing patient-specific reminders delivered at the point-of-care, with one-page treatment guidelines endorsed by local opinion leaders ("Local Opinion Leader Statement"). This trial is designed to evaluate the impact of these Local Opinion Leader Statements on the practices of primary care physicians caring for patients with coronary disease. In order to isolate the effects of the messenger (the local opinion leader) from the message, we will also test an identical quality improvement intervention that is not signed by a local opinion leader ("Unsigned Evidence Statement") in this trial. METHODS: Randomized trial testing three different interventions in patients with coronary disease: (1) usual care versus (2) Local Opinion Leader Statement versus (3) Unsigned Evidence Statement. Patients diagnosed with coronary artery disease after cardiac catheterization (but without acute coronary syndromes) will be randomly allocated to one of the three interventions by cluster randomization (at the level of their primary care physician), if they are not on optimal statin therapy at baseline. The primary outcome is the proportion of patients demonstrating improvement in their statin management in the first six months post-catheterization. Secondary outcomes include examinations of the use of ACE inhibitors, anti-platelet agents, beta-blockers, non-statin lipid lowering drugs, and provision of smoking cessation advice in the first six months post-catheterization in the three treatment arms. Although randomization will be clustered at the level of the primary care physician, the design effect is anticipated to be negligible and the unit of analysis will be the patient. DISCUSSION: If either the Local Opinion Leader Statement or the Unsigned Evidence Statement improves secondary prevention in patients with coronary disease, they can be easily modified and applied in other communities and for other target conditions.

Journal Article↗

Standardization of early drug trials in allergic diseases (with reference to a trial of doxantrazole).

Attention is drawn to the long wait in certain countries before new drugs and other therapies for the treatment of allergic diseases are approved by the local authorities, even when good trials with them have been carried out elsewhere. The main reasons for requiring repeat trials are poor original case selection and inadequate parameters of assessment, particularly environmental variations. The results of re-assessing patients who in the previous year had undergone a trial of a new chromoglycate-like drug (Doxantrazole) are used to illustrate the need to introduce standard basic requirements when new drugs and other agents are being tested in allergic diseases. A suggested format of such requirements is presented.

Bronchodilator Agents↗

Clinical trials with diglycoaldehyde (NSC-118994): review and reasons for withdrawal from clinical trial.

All Phase II studies with diglycoaldehyde with leukemia and solid tumors have been reviewed. The dose schedules employed ranged from 1.5 to 2.0 g/m2/day for 3 to 5 days. The most common side effects have been gastrointestinal (nausea and vomiting), which occurred in 22% of the patients. Renal toxicity (rise in BUN, creatinine, and urinary proteins) was seem in 17% of the patients treated. Other infrequent toxicities include hypocalcemia (9%) and local complications such as phlebitis. Leukopenia, thrombocytopenia, positive Coombs' test and impairment in coagulation profile were also reported. In contrast to the hints of therapeutic efficacy described during Phase I trials, in phase II trials no activity was noted among 96 patients with solid tumors and only minimal antileukemic action among 49 other patients. These disappointing Phase II trials coupled with prominent toxicities have prompted the decision to terminate further clinical testing. This report summarizes all clinical observations as an example of circumstances which curtail clinical testing of anticancer drugs.

Aldehydes↗