Principles Of Good Clinical Practice Research Articles

Ice cooling challenge as a means to probe skin microvascular function

Skin microvasculature provides a window to study both systemic and local physiology. In vascular medicine, various challengers such reactive hyperemia, hypoxia or hyperoxia, and heat, have been used to study function and search for potential clinical biomarkers. A positive relationship between increased skin temperature and skin perfusion has been suggested, but skin cooling as a challenger has not been well explored. In the present study, the adaptive cardiovascular and hemodynamic impacts of single hand cooling were examined in a group of ten healthy women, 27.3±7.9 years old, of normal body mass index and ankle-brachial index, normotensive, non-smoking, and free from any medication and supplements. The study followed all principles of good clinical practice and ethics commission approval. After complete stabilization, a participant’s palm, randomly chosen, was placed in contact with a frozen surface covered by a plasticized cotton cloth. Blood perfusion was measured using a laser Doppler flowmetry (LDF) instrument, and temperature were continuously registered in both hands, before, during, and after (early and late recovery) the ice cooling challenge. Nominal values for blood perfusion and temperature were considered, as well as their wavelet transform (WT) components, translating endothelial [0.0095; 0.021] Hz, autonomic [0.021; 0.052] Hz, myogenic [0.052; 0.015] Hz, respiratory [0.15; 0.6] Hz, and cardiac [0.6; 2] Hz activities. No significant differences were observed between limbs regarding nominal LDF values for each experimental phase. Nonetheless, significant differences were observed for nominal temperature signals between limbs during the challenge (Wilcoxon’s signed rank test; p=0.047), and for early (p=0.028) and late (p=0.028) recovery phases. Significant differences were observed for ipsi- and contralateral LDF signals (Friedmann’s test, p<0.001, and p=0.012, respectively), and also for ipsi- and contralateral temperature signals (Friedmann’s test, p<0.001, and p=0.004, respectively). These contralateral responses have been previously described with other challengers applied only in the ipsilateral limb, whilst it is known that local cooling stimulates cutaneous thermoreceptors, sympathetic nerve activity and cutaneous vascular resistance. However, our findings also show that temperature may be more sensitive than LDF for studying the ice cooling challenge, and that the WT analysis approach can provide potential physiological interpretations. Nonetheless, a strong positive correlation (Spearman’s rs = 0.820, p<0.001) was observed between temperature and LDF signals overall for both limbs. In conclusion, this preliminary study suggests that this cooling challenger is effective to elicit vascular physiological changes in both limbs, indicating a putative centrally-mediated adaptive process that might be quantified by changes in cardiac and respiratory activities, as shown from WT analysis. Additionally, temperature signals and the use of WT analysis seem to provide more sensitive and explanatory insights than the use of LDF signals and nominal values alone. Suported by COFAC/ALIES. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Light physical activity improves lower limb perfusion asymmetries in older sedentary adults — an exploratory study

Perfusion asymmetries between lower limbs are common even in healthy young individuals, although their physiological significance is unknown. Even in the absence of vascular disease, ageing is among the determinants that seem to accentuate those differences. While it is known that physical activity affects vascular hemodynamics, its specific impact on perfusion asymmetries in healthy elderly individuals is still unclear. This study aimed to identify vascular asymmetries and their variations after a regular program of light exercise in older individuals with age-related comorbidities in the absence of peripheral vascular disease (PVD). Ten participants, mean age 62.4 ± 5.6 years old, were selected following specific criteria. Participants were mostly sedentary, combining one or more common morbidities for this age group — in particular hypertension, overweight and / or diabetes (T2D). Exclusion criteria were an abnormal Ankle-Brachial Index assessed in a standing position at rest and evidence of compromised mobility. All procedures respected the principles of good clinical practice, being previously submitted and approved by the institutional Ethical Commission. Lower limb perfusion was assessed in both feet (anteromedial region) at two time points — day zero (D0) and thirty days later (D30) — using two optical-based technologies — Laser Doppler Flowmetry (LDF) and Polarized Spectroscopy (PSp). These two technologies measure at different depths, with LDF providing deeper tissue readings. During this evaluation period, participants underwent a daily structured program of light exercises based on the FITT principles (F, frequency; I, intensity; T, time and T, type of activity/activity performance) centred in the lower limb perfusion. The group revealed significant asymmetries at D0, where the right foot consistently showed higher values with both technologies correlating positively. At D30, LDF values increased by 57.5% in both feet, meaning that asymmetries disappeared. No significant changes were observed with PSp. Basic cardiovascular functions such as blood pressure and mean arterial pressure were also evaluated, showing significant decreases in systolic pressure and mean arterial pressure. These encouraging results suggest that regular physical activity, even if light in intensity and duration, improves overall hemodynamics and specifically raises perfusion in the lower limbs. These findings should be further explored with the aimof prevention and treatment of PVD. This research was financed by national funds through FCT - Foundation for Science and Technology, I.P. (Portugal), under the [UIDB/04567/2020] and [UIDP/ 04567/2020] programs. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Skin closUre in carPal tunnEl Release (SUPER): protocol for a blinded randomised controlled trial comparing absorbable and non-absorbable sutures in carpal tunnel release

IntroductionCarpal tunnel syndrome is a common disorder affecting a substantial portion of the general population. Surgical intervention is often deemed necessary, with the median nerve release being one of the...

Multicentre randomised trial of screening with sFlt1/PlGF and planned delivery to prevent pre-eclampsia at term: protocol of the PE37 study

IntroductionPre-eclampsia affects ~5%–7% of pregnancies. Although improved obstetric care has significantly diminished its associated maternal mortality, it remains a leading cause of maternal morbidity and mortality in the world. Term...

Interventional embolisation for patients with cirrhosis and recurrent or persistent hepatic encephalopathy related to spontaneous portosystemic shunts: protocol for a prospective, non-randomised controlled study

IntroductionThe presence of spontaneous portosystemic shunts (SPSS) has been identified to be associated with hepatic encephalopathy (HE) in patients with cirrhosis. Nevertheless, the role of interventional embolisation in managing such...

ProFertil study protocol for the investigation of gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy aiming at fertility protection of young women and teenagers with cancer in Sweden—a phase III randomised double-blinded placebo-controlled study

BackgroundGonadotropin-releasing hormone agonists (GnRHa) cotreatment used to transiently suppress ovarian function during chemotherapy to prevent ovarian damage and preserve female fertility is used globally but efficacy is debated. Most clinical...

PREDICTIVE FACTORS AND CLINICAL AND PARACLINICAL FEATURES OF URINARY TRACT DYSFUNCTION IN PRETERM INFANTS

PREDICTIVE FACTORS AND CLINICAL AND PARACLINICAL FEATURES OF URINARY TRACT DYSFUNCTION IN PRETERM INFANTS

Academia and industry agreement on a feasibility tool for first-time-in-human clinical trial units.

First-time-in-human (FTIH) trials are designed to generate information on the safety, tolerability, as well as the pharmacokinetic and pharmacodynamics profile of new drugs. To ensure the safety of participants, these trials need to be conducted at specifically equipped phase I clinical trial units (CTUs). In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) and the European Union (EU) regulatory guidelines, one of the aims of the European Regime Accelerator for Tuberculosis (ERA4TB) project is to collaboratively create a feasibility tool, through a partnership between public and private entities, for the validation of CTUs selected to conduct FTIH trials. A feasibility form, encompassing nine sections, was created to gather information on the unit in relation to key attributes of FTIH trials. Collaboratively, industry and academic partners defined the minimal criteria to ensure the adherence of CTUs to the principles of ICH GCP and regulations outlined by the European Medicines Agency (EMA) for the execution of FTIH trials. Subsequently, all CTUs available for the project were assessed for FTIH trial eligibility. The introduction of the certification procedure through the feasibility tool within ERA4TB resulted in the accreditation of the five academic CTUs, which are now prepared to carry out FTIH trials as part of the Consortium. The developed feasibility tool aims to establish open and widely used minimum requirements for the validation of academic CTUs as FTIH units, marking it as the inaugural tool for CTU validation resulting from the collaboration between industry and academia within the ERA4TB project. The established partnership has enabled an innovative and novel way of working.

Protocol for a double-blinded randomised controlled trial investigating the use of adjunct bicarbonate in carpal tunnel release: a single-centre study

IntroductionThis study aims to compare the effectiveness of buffered and non-buffered long-acting local anaesthetics in pain relief during and after carpal tunnel release (CTR) surgery. Carpal tunnel syndrome (CTS) is...

Value of indomethacin suppository for preoperative analgesia and anti-inflammation in laparoscopic appendectomy: a protocol of prospective, double-blinded, single-centre, randomised controlled trial in China

IntroductionPostoperative pain has always been a problem for patients and surgeons. Local inflammation, surgical trauma and pain in the body can cause a systemic stress response and immune imbalance, which...

The Bioequivalence Study of Two Dexketoprofen 25 mg Film-Coated Tablet Formulations in Healthy Males Under Fasting Conditions.

Dexketoprofen is a non-steroidal analgesic/anti-inflammatory drug and its trometamol salt is extensively preferred in mild or moderate pain due to its rapid onset of relief. A new formulation of 36.9 mg of dexketoprofen trometamol (equivalent to 25 mg dexketoprofen) tablet has been developed and its bioequivalence to the reference product was proven. An open-label, single-dose, randomized, two-period, and cross-over bioequivalence study was conducted with healthy males under fasting conditions for two different tablet formulations of 25 mg dexketoprofen. To prove the bioequivalence of the test product with the reference product, a comparison study has been performed in compliance with regulations in force under Good Clinical Practice principles. A single-center clinical study was run and blood samples of the participants were withdrawn at specified time points, before and after dosing, to measure the plasma concentrations of dexketoprofen trometamol. A validated analytical method has been developed using an liquid chromatography with tandem mass spectrometry. Instrument to assess the plasma concentrations of the test and reference products. Forty-seven volunteers completed clinical phase of the study. For the test and reference products, the mean ± standard deviations (SD) of Cmax were found 2543.82 ± 655.42 ng/mL and 2539.11 ± 662.57 ng/mL, and the mean ± SD of area under the curve (AUC) from time 0 to the last measurable concentration (AUC0-tlast) were found 3483.49 ± 574.42 h.ng/mL and 3560.75 ± 661.83 h.ng/mL, respectively. The primary target variables data demonstrate the bioequivalence of test and reference products with regard to 90% confidence interval for Cmax of 92.45-108.53% and for AUC0-tlast of 95.57-100.87%. The geometric mean ratios were found as 100.16% and 98.18% for Cmax and AUC0-tlast, respectively. There were no serious adverse events or adverse reactions reported throughout the study. After statistical evaluation of the analytical results, the test and reference products were considered bioequivalent. Both products were well tolerated and considered as safe.

“How do I keep this live in my mind?” Allied Health Professionals’ perspectives of barriers and enablers to implementing good clinical practice principles in research: a qualitative exploration

BackgroundAllied health professionals (AHPs) engaged in research are expected to comply with Good Clinical Practice (GCP) principles to protect participant safety and wellbeing and enhance data integrity. Currently, few studies have explored health professionals’ perceptions of implementing and adhering to GCP principles in research with none of these including AHPs. Such knowledge is vital to guide future interventions to increase adherence to GCP principles. This study aimed to identify the barriers and enablers AHPs experience when applying GCP principles to research conduct in a public hospital and health service, as well as their perceived support needs.MethodsThe study used a qualitative descriptive study approach guided by behaviour change theory. AHPs currently undertaking ethically approved research within a public health service in Queensland, Australia were interviewed to explore barriers and enablers to adherence to GCP principles and support needs, with interview questions guided by the Theoretical Domains Framework (TDF). The TDF was chosen as it allows for a systematic understanding of factors influencing implementation of a specific behaviour (i.e., GCP implementation) and can be used to inform tailored interventions.ResultsTen AHPs across six professions were interviewed. Participants identified both enablers and barriers to implementing GCP across nine domains of the TDF and enablers across three additional domains. Examples of enablers included strong beliefs about the importance of GCP in increasing research rigour and participant safety (i.e. from TDF - beliefs about consequences); applying clinical skills and personal attributes when implementing GCP (i.e., skills), available training and support (i.e., environmental context and resources); and alignment with their moral sense to ‘do the right thing’ (i.e., professional identity). Barriers to GCP implementation were generally less commonly reported but included reduced time to implement GCP and a sense of ‘red tape’ (i.e., environmental context and resources), a lack of knowledge of GCP principles (i.e., knowledge) and a fear of making mistakes (i.e., emotions), and varying relevance to individual projects (i.e., knowledge). Suggestions for support were identified beyond training, such as physical resources (e.g., prescriptive checklists, templates and scripts), additional time, and regular one-on-one mentoring support.ConclusionFindings suggest that while clinicians recognise the importance of GCP and want to implement it, they report barriers to its practical implementation. GCP training alone is unlikely to address these barriers to implementing GCP in daily practice. Findings suggest that GCP training may be more useful to AHPs when it is tailored to the allied heath context and supplemented with additional supports including check-ups from experienced researchers and access to prescriptive resources. Future research however is needed to investigate the effectiveness of such strategies.

The results of the pilot project to create a system for monitoring the health and rehabilitation of employees of JSC "Russian Railways" with sensorineural hearing loss

The activity of employees of locomotive crews is characterized by the presence of a number of production factors adversely affecting the state of health, which include noise. It provokes the development of hearing loss. The study aims to evaluate the effectiveness of rehabilitation of railway workers with sensorineural hearing loss. 70 employees of locomotive crews with sensorineural hearing loss took part in the work. Before and after the course of preventive treatment, all participants in the pilot study underwent a medical examination at the Russian Railways-Medicine healthcare facilities, including an examination by an otorhinolaryngologist, and tonal audiometry was performed. Patients received rehabilitation according to an individual program. Upon completion of the course of treatment, all participants of the pilot project noted a decrease in noise in the head and ears, a decrease in headache, normalization of sleep. When analyzing the dynamics of the audiometric picture 43 employees (61.4%) showed positive dynamics. The conducted research shows the effectiveness of the pilot project on the implementation of preventive measures for employees who are at risk for the development of occupational diseases. This project contributes to the preservation of the professional longevity of the company's employees. Ethics. The researchers conducted this study in accordance with the principles of good clinical practice. The Interuniversity Ethics Committee approved the study by decision (Protocol No. 09-21 of 10/21/2021).

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Trends of Phase I Clinical Trials in the Latest Ten Years across Five European Countries.

Phase 1 clinical trials represent a critical phase of drug development because new candidate therapeutic agents are tested for the first time on humans. Therefore, international guidelines and local laws have been released to mitigate and control possible risks for human health in agreement with the declaration of Helsinki and the international Good Clinical Practice principles. Despite numerous scientific works characterizing the registered clinical trials on ClinicalTrials.gov, the main features and trends of registered phase 1 clinical trials in Europe have not been investigated. This study is aimed at assessing the features and the temporal trend of distribution of phase 1 clinical studies, carried out in the five largest European countries over a ten-year period (2012-2021), and to evaluate the impact of the Italian regulatory framework on the activation of such studies. The main data and characteristics of phase 1 clinical studies registered on the ClinicalTrials.gov database for France, Germany, Italy, Spain and the United Kingdom have been investigated and subsequently compared. The above-mentioned countries were selected based on similarities in terms of demographic and Gross Domestic Product (GDP) data available on official government websites. (3) Results: A total number of 6878 phase 1 clinical trials were registered for the five selected countries in the ClinicalTrials.gov database during the ten years analyzed; the studies were predominantly randomized (39.33%) and for-profit (76.64%). The most represented area of investigations was oncology (52.15%), followed by hematology (24.99%) and immunology (12.04%). The variability observed between the analyzed countries showed that the UK, Germany and France presented the highest reduction in the number of phase 1 clinical trials, while for Spain and Italy, a stable/increased trend was observed, although with a lower number of trials registered on the ClinicalTrials.gov database. (4) Conclusions: Italy displayed the lowest number of registered phase 1 clinical trials, even though it showed a stable trend over the years. In this regard, the Italian regulatory framework must urgently be adapted to that of other European countries (Spain has been the first country to implement the new Regulation (EU) No 536/2014) and streamline the process of clinical trial application to increase the attractiveness of the country. Moreover, nonprofit phase 1 clinical trials (which represent 19.81% of the total number of phase 1 clinical trials registered in Italy vs. 80.19% of profit phase 1 clinical studies) should be promoted and supported by the institutions, even from a financial point of view, to allow independent researchers to develop new therapeutic drugs.

Optoacoustic Imaging Offers New Insights into In Vivo Human Skin Vascular Physiology.

Functional imaging with new photoacoustic tomography (PAT) offers improved spatial and temporal resolution quality in in vivo human skin vascular assessments. In the present study, we followed a suprasystolic reactive hyperemia (RH) maneuver with a multi-spectral optoacoustic tomography (MSOT) system. A convenience sample of ten participants, both sexes, mean age of 35.8 ± 13.3 years old, was selected. All procedures were in accordance with the principles of good clinical practice and approved by the institutional ethics committee. Images were obtained at baseline (resting), during occlusion, and immediately after pressure release. Observations of the RH by PAT identified superficial and deeper vascular structures parallel to the skin surface as part of the human skin vascular plexus. Furthermore, PAT revealed that the suprasystolic occlusion impacts both plexus differently, practically obliterating the superficial smaller vessels and evoking stasis at the deeper, larger structures in real-time (live) conditions. This dual effect of RH on the skin plexus has not been explored and is not considered in clinical settings. Thus, RH seems to represent much more than the local microvascular reperfusion as typically described, and PAT offers a vast potential for vascular clinical and preclinical research.

First-Trimester Sequential Screening for Preeclampsia Using Angiogenic Factors: Study Protocol for a Prospective, Multicenter, Real Clinical Setting Study.

IntroductionThe incidence of preeclampsia (PE) is about 2–8%, making it one of the leading causes of perinatal morbidity and maternal mortality in the world. Early prophylactic low dose administration (150 mg) of acetylsalicylic acid is associated with a significant reduction in the incidence of early-onset PE, intrauterine growth restriction (IUGR), and neonatal mean stay in the intensive care unit (ICU). Universal implementation of a first-trimester screening system including angiogenic and antiangiogenic markers [the Placental Growth Factor (PlGF) and/or soluble fms-like Tyrosine Kinase-1 (sFlt-1)] has shown a prediction rate of 90% for early-onset PE but entails a high financial cost. The aim of this study is to determine the predictive and preventive capacity of a universal PE first-trimester two-step sequential screening model, determining the PlGF only in patients previously classified as intermediate risk by means of a multivariate model based on resources already used in the standard pregnancy control, in a real clinical setting. We hypothesize that this screening model will achieve similar diagnostic performance as the universal determination of PlGF but at a lower economic cost.Methods and AnalysisThis is a prospective, multicentric, cohort study in a real-world clinical setting. Every singleton pregnancy will be recruited at the routine first pregnancy visit. In a first step, the first-trimester risk of PE will be calculated using a multivariate Gaussian distribution model, based on medical history, mean blood pressure, Pregnancy-Associated Plasma Protein A (PAPP-A), and Uterine Artery Doppler Pulsatility Index (UTPI). Patients will be classified into three risk groups for PE: (1) risk ≥ 1/50, high-risk with no further testing (blinded PlGF); (2) risk between 1/51 and 1/500, medium-risk requiring further testing; and (3) risk ≤ 1/501, low-risk with no further testing. In a second step, the PlGF will only be determined in those patients classified as intermediate risk after this first step, and then reclassified into high- or low-risk groups. Prophylactic administration of aspirin (150 mg/day) will be prescribed only in high risk patients. As a secondary objective, sFlt-1 values will be blindly determined in patients with high and intermediate risk to assess its potential performance in the screening for PE.Ethics and DisseminationThe study will be conducted in accordance with the principles of Good Clinical Practice. This study is approved by the Aragon Research Ethics Committee (CEICA) on 3 July 2020 (15/2020).Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT04767438.

Short duration – low intensity isometric plantar flexion increases distal perfusion: observations from a healthy cohort

Controlled physical activity might help as a preventive and therapeutic tool in vascular pathology. In this study we aimed to understand how lower limb exercise impacts perfusion in a healthy cohort. The study involved a convenience sample of eighteen previously selected healthy individuals of both sexes (n=9 each), mean age 32.8 ± 12.7 years. Procedures respected all principles of good clinical practice. Blood perfusion changes were simultaneously assessed in the dorsal region of both feet by laser Doppler flowmetry (LDF) and polarised spectroscopy (PSp). Measurements were taken at baseline, after stabilization (phase I), following 1 minute of bipedal isometric plantar flexion (phase II), and during recovery (phase III). Descriptive and comparative statistics were performed. Plantar flexion evoked significant perfusion changes in both feet, but in opposite directions – increasing with LDF and decreasing with PSp. These changes indicate that this approach promotes an adaptive mobilisation of blood from superficial to the deeper plexus. No significant changes in arterial blood pressure or cardiac frequency were detected. This manoeuvre, needing no specialised supervision, is capable of promoting significant perfusion changes in the lower limb, showing potential to be further explored in future studies with a prospective design in a preventive/recovery context. Keywords: plantar flexion; foot perfusion; laser Doppler flowmetry; polarised spectroscopy; PAHR - prompt adaptive hemodynamical response; physical activity; home-health

Transplantation Without Overimmunosuppression (TWO) study protocol: a phase 2b randomised controlled single-centre trial of regulatory T cell therapy to facilitate immunosuppression reduction in living donor kidney transplant recipients

IntroductionRegulatory T cell (Treg) therapy has been demonstrated to facilitate long-term allograft survival in preclinical models of transplantation and may permit reduction of immunosuppression and its associated complications in the...

Value of ultra-high field MRI in patients with suspected focal epilepsy and negative 3\xa0T MRI (EpiUltraStudy): protocol for a prospective, longitudinal therapeutic study

PurposeResective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). MethodsWe present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up.ResultsAll patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded.ConclusionThis protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences.Trial registration numberwww.trialregister.nl: NTR7536.