BIA research studies -
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was unwilling or unable to give written informed consent. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. gov identifier NCT number : NCT Layout table for location information France Biotrial's Human Pharmacology Unit Rennes, France, F More Information.
Layout table for additonal information Responsible Party: Bial - Portela C S. gov Identifier: NCT Other Study ID Numbers: BIA First Posted: March 27, Key Record Dates Last Update Posted: March 27, Last Verified: March Individual Participant Data IPD Sharing Statement: Plan to Share IPD: Undecided Layout table for additional information Studies a U.
FDA-regulated Drug Product: No Studies a U. FDA-regulated Device Product: No Additional relevant MeSH terms:. Layout table for MeSH terms Heart Failure Cardiovascular Diseases Heart Diseases. For Patients and Families For Researchers For Study Record Managers. Home RSS Feeds Site Map Terms and Conditions Disclaimer Customer Support.
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Recruitment Status : Completed First Posted : March 27, Last Update Posted : March 27, Hypertension Congestive Heart Failure. Drug: BIA Phase 1. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Comparative Bioavailability Study of BIA Under Fasted and Fed Conditions.
Actual Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. Experimental: BIA Fasting BIA mg in fasting conditions. Oral bioavailability was not reported. Terminal half-life persistence in the blood of the BIA 10— in rats was 45 hours oral or 4 hours i.
and in dogs it was hours oral or 52 hours i. The authors made no prediction of a likely half-life in humans. Around two-thirds of the total dose was eliminated in the urine , about one-fifth in the faeces and the remainder was heavily metabolized in all species studied rat, mouse, dog, monkey.
Metabolism of BIA was essentially complete by 72 hours. Main metabolites were not described. The studies used total detectable radioactivity to calculate half-life and did not assess what proportion of this was due to metabolites.
The preliminary report by the French Inspector General for Social Affairs IGAS , for the French Ministry of Health, remarked on the difference between the rat oral vs. half life, and, that in light of the adverse events seen in humans on repeated dosing, this may indicate "a mechanism of accumulation".
The molecule showed non-linear pharmacokinetics at doses between 40 and mg, suggesting elimination pathways had become saturated, leading to accumulation. The final report by the ANSM Committee noted the drug had a very steep dose-effect curve in humans "going from absence of to almost complete inhibition" over a narrow concentration range.
The protocol presents a summary of safety pharmacology studies in two species rat, dog and repeated dose toxicity studies in four species week sub-chronic studies in mouse, dog and monkey; a week chronic study in the rat. The authors suggest that these were the maximum doses tested in these studies, though it is not clear.
The protocol nominates a human NOAEL of mg as a human equivalent dose to the week rat NOAEL, though with no description how this was calculated. The summary presented however includes no assessment of the relevance of the animal species selected for study that is, in terms of physiological and genetic similarities with humans and the mechanism of action of the study drug.
At a hearing convened by the ANSM in March , Bial clarified that the apparently extensive animal toxicology studies and number of species was due to a delay in commencement of clinical development, thus some studies had already been completed that would not have been required for a Phase I study.
The ANSM Committee found no evidence that the studies had been performed because the company had doubts as to the tolerance of the molecule. Notably absent from the protocol were calculations of receptor occupancy; predictions of in vivo ligand binding saturation levels; measures of target affinity or assessment of non-target binding interactions as suggested by the European guidance for Phase I studies depending on whether BIA could be considered to require 'special consideration' as outlined in the guideline.
In fact, the trial tested doses up to 80 times more mg BIA 10— than should have been required. Although the protocol summary reports no animal deaths during the studies, the ANSM expert committee reported that in fact several monkeys died or had to be euthanised during the dose escalation studies and that an explanation from Bial was pending.
Also, two animals had to be euthanised in the week dog study due to lung lesions - both from the top dose group. It is not clear whether Bial disclosed these adverse animal findings either to Biotrial or to the ANSM in their application for clinical trial authorisation.
The findings presented in the trial protocol provide no explanation for the type and severity of events that would be later observed in Rennes. The Minister described this as an opportunity for improvement.
The final report by the ANSM Committee concluded regarding the preclinical studies that "no aspects of the data that the TSSC has studied constituted a signal likely to contraindicate administration in humans.
This is highly surprising given the regulatory importance of this document. In Biotrial, a contract research organization , initiated a first-in-human trial of BIA 10— in healthy volunteers, with secondary endpoints to investigate neuropathic pain.
The study was entitled "A double-blind, randomised, placebo-controlled, combined single and multiple ascending dose study including food interaction, to investigate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of BIA , in healthy volunteers".
The trial commenced on 9 July at a single centre in the city of Rennes , and commenced recruitment of healthy volunteers, both men and women aged 18 to The protocol describes four distinct parts to the study:.
The protocol specifies the first three parts would be double-blind but the pharmacodynamics part would be open label. According to the protocol, dose levels and numbers of groups could be increased, or were not yet defined, and would depend on what was observed with initial dosing, an approach known as adaptive trial design.
Thus many details of the key multi-dose part are not included in the trial protocol. For the single dose part of the study, the protocol describes eight groups of eight volunteers randomised who were to receive single doses of BIA 10— at 0.
The protocol provides for the first two subjects of the first single dose cohort to receive the first dose as a sentinel dose, that is, either 0. In the event no safety concerns had emerged in the foregoing, all other single- and multi-dose groups were to be dosed with a minute interval between recipients.
For the multiple ascending dose part of the study, the protocol planned four groups of eight volunteers randomised who were to receive a single dose orally, once daily for 10 days at different dose levels. However, the protocol defines no doses for these groups, stating that this will be based on the outcome of the single dose portion of the trial.
Further dose groups up to a maximum of eight groups could be added depending on whether adverse events were observed.
Further details of the study as it was actually conducted have been published by the French agency ANSM. The dose groups for the single dose part were as described in the protocol, with no additional groups undertaken. In the crossover part, a single 40 mg dose was given to a group of 12 subjects.
In the multiple dose ascending part, the doses were 2. The severe adverse events were observed in the 50 mg dose group. The ANSM expert committee reported [15] that complete FAAH inhibition should have been achieved by a dose of 1.
Further, the ANSM committee remarked that the gap between the 20 mg and 50 mg dose cohorts, in effect, skipped a dose based on extrapolation from the single dose part of the study, and that the progression to 50 mg was too large a jump.
On reviewing the subject data from the trial itself, the committee noted that BIA showed non-linear pharmacokinetics at doses between 40 and mg that is, the molecule appeared to be accumulating at higher doses and that most likely the elimination mechanism had become saturated.
Thus dosing at 50 mg daily was - each day - 40 times more than required to achieve complete inhibition, and in practice this dose level resulted in accumulation. According to Bial and the Rennes University Hospital, by the time the serious adverse reactions emerged, subjects had been recruited and 84 other volunteers had received the drug during the trial, with no serious adverse events being reported.
fasting part, and the first four dose groups of the multi-dose part of the study had each been completed in Notably, the administration of 20 mg BIA once daily for 10 consecutive days elicited no serious adverse events in the six volunteers who received it.
Dosing of eight volunteers in the highest multi-dose group in the BIA trial commenced on 6 January Six of the participants received 50 mg per day of the drug while two received placebo.
On the following day, the other subjects received a 6th dose at am before the trial was suspended later that day 11 January. The fifth dose level 50 mg per day for 10 days of the multi-dose part of study had been underway for five days when the first volunteer became ill and was hospitalized at the Rennes University Hospital on the evening of 10 January with symptoms similar to a stroke.
All the MRI findings, though widely varying in severity, were of the same form and seen in the hippocampus and pons of the affected individuals. The men who were hospitalised were all from the group which received the highest dose of the multiple ascending part of the trial.
A neurologist at the University of Rennes Hospital Center, Professor Pierre-Gilles Edan, stated in a press conference with the French Minister for Health, that 3 of the 4 men who were displaying neurological symptoms "already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap" and were being given corticosteroids to control the inflammation.
The man who died was later named by local news media as Guillaume Molinet, 49, an artist and father of four from Guilliers, a town in the Breton department of Morbihan. Molinet's family said they were originally told he had had a stroke that was unrelated to the clinical trial, though this quickly turned out not to be the case.
The events in Rennes were made public on 15 January [1] [3] [4] and were reported widely in the media in France, [41] [42] [43] internationally in mainstream news [44] [45] [46] [47] and scientific media.
The journal Nature quoted Bial spokeswoman Susana Vasconcelos as saying the trial had been conducted "in accordance with all the good international practices guidelines, with the completion of tests and preclinical trials" and that "the company is committed to determine thoroughly and exhaustively the causes which are at the origin of this situation".
The journal also sought comment from Jean-Marc Gandon, the president and chief executive of the CRO Biotrial, who said "he cannot immediately respond to queries from Nature, that he is focused on trying to save the patients and that the company will respond later".
As of March it remained unclear whether Bial disclosed the adverse animal findings to Biotrial, including the deaths of monkeys and dogs in several studies.
François Peaucelle, the director general of Biotrial, is reported to have told Le Figaro. From that data, there was nothing worrying in view of the dosage we were administering to humans. The Agence Nationale de Sécurité du Médicament ANSM announced an investigation, and that an inspection of the trial site was already underway.
The ONIAM Office National d'Indemnisation des Accidents Médicaux , responsible for medical injury compensation, stated only 10 accidents had occurred during clinical trials over the past 15 years per its records, and that those cases had "consequences infinitely less serious" than the incident in Rennes.
Initial reports from the authorities suggested that the causes of the brain injuries was likely to be due to the mechanism of BIA and the doses employed in the trial. In May , the French Health Minister announced several new measures for clinical trials in France, including the establishment of an expert group within the ANSM for review of first in human and early phase studies.
The Inspection générale des affaires sociales IGAS released a preliminary report on 5 February The Minister announced that all clinical trials in France in the event of a serious, unexpected adverse event such as this would be explicitly required to re-consent the remaining trial participants.
Biotrial published a detailed response on its website, expressing its disappointment to learn of the report via the media and not prior to its publication from the Health Ministry. CHU informed Biotrial at am on 11 January that the man had likely had a stroke , at which point the trial was halted, though it was not known whether the stroke had anything to do with the study drug.
This was after further doses had been given to the other volunteers at am that morning. Biotrial's statement offered no comment on the time taken between the trial halt at am on the 11th and the notification of the authorities three days later on the 14th.
The committee also criticised the clinical study design which "probably significantly contributed to the accident", noting that administration of the top multi-dose groups did not and could not take into account emerging pharmacokinetic data from latest dose groups and offered no chance to adjust the dose as adverse events emerged.
The choice of dose escalation levels 20 to 50 to mg was based on pharmacokinetic data from the 10 mg group and data from the 50 mg dose group that would have clearly shown non-proportional dose kinetics were not yet available when administration to the mg multi-dose group commenced.
The committee made six recommendations, which it invited European and International regulators to consider reproduced here in brief :.
A European Medicines Agency EMA spokesperson said in January that "EU authorities will look carefully at the findings to determine if further measures are needed to protect health of clinical trial participants. Until EU authorities have the full picture, it is not possible to say whether any revisions to EU guidelines are required".
The European Investment Bank , which provided million euros in funding for Bial's FAAH inhibitor programme stated it had been in contact with the company about the incident, but that "it would be premature to consider recall of the EIB loan at this stage". The US Food and Drug Administration issued a statement that it was in contact with its counterparts the ANSM as well as the EMA and announced investigations into FAAH inhibitors as a drug class.
FDA will work with sponsors to ensure the safety of participants in clinical studies and take regulatory action as appropriate. The German drug regulator, the Bundesinstitut für Arzneimittel und Medizinprodukte BfArM issued a statement 19 January that no clinical trials with FAAH inhibitors were underway in Germany, but that it had authorised seven such trials previously, which were completed without serious incidents.
The Rennes University Hospital provided updates on the remaining volunteers in the study and the treating specialists later published a medical report describing the sickened volunteers in November in The New England Journal of Medicine.
The authors were of the view that "the toxic effects we observed were related to drug accumulation. This hypothesis is supported by the nonlinear pharmacokinetics of BIA for doses higher than 40 to mg" and as reported by the ANSM's expert committee.
The authors were not however granted access to information from the post-mortem of the man who died. News reports from March described the condition of Stéphane Schubhan 42 , a professional photographer from La Flèche , Sarthe and participant of the top dose cohort.
Schubhan "sleeps badly, has nightmares, sees double at all times, walks with difficulty, and succumbs to dizziness and nausea if he stands more than 10 minutes at a time" and does not know if he will be able to work again.
Schubhan said he had participated in a previous clinical trial, but in this case he was never informed about the animal deaths that were later revealed and would never have consented to take part had he known.
Doctors have told Schubhan that they hope he will improve over the coming 6—12 months but that they do not know what the outcome will be [26]. In , Mr. Schubhan was convicted and sentenced to 30 years jail for the attempted murder of his partner and children's mother, whom he was planning to leave.
Under French Law, all clinical trial participants are protected by the Huriet Law on the protection of persons in clinical research. Herrington S, Brussoni M. Beyond physical activity: the importance of play and nature-based play spaces for children's health and development.
Curr Obes Rep. Casolo A, Sagelv EH, Bianco M, Casolo F, Galvani C. Effects of a structured recess intervention on physical activity levels, cardiorespiratory fitness, and anthropometric characteristics in primary school children.
J Phys Educ Sport. Guerra PH, Nobre MR, Silveira JA, Taddei JA. The effect of school-based physical activity interventions on body mass index: a meta-analysis of randomized trials. Vaquero-Solís M, Gallego DI, Tapia-Serrano MÁ, Pulido JJ, Sánchez-Miguel PA. School-based physical activity interventions in children and adolescents: a systematic review.
Int J Environ Res Public Health. Rhea DJ, Rivchun AP. The LiiNK Project®: effects of multiple recesses and character curriculum on classroom behaviors and listening skills in Grades K-2 children.
Front Educ. CrossRef Full Text Google Scholar. Lund E, Brimo D, Rhea D, Rivchun A. The effect of multiple recesses on listening effort: a preliminary study.
J Pediatr Educ Rehabil Audiol. Clark L, Rhea D. The LiiNK Project ® : comparisons of recess, physical activity, and positive emotional states in Grade K-2 children. Int J Child Health Nutr. Farbo D, Rhea D. Texas Christian University Farbo D, Maler LC, Rhea DJ. The preliminary effects of a multi-recess school intervention: using accelerometers to measure physical activity patterns in elementary children.
Katzmarzyk PT, Barreira TV, Broyles ST, Champagne CM, Chaput JP, Fogelholm M, et al. Physical activity, sedentary time, and obesity in an international sample of children.
Med Sci Sports Exerc. Oliveira LC, Ferrari G, Araújo TL, Matsudo V. Overweight, obesity, steps, and moderate to vigorous physical activity in children. Rev Saude Publ. Let's Inspire Innovation N' Kids. Borga M, West J, Bell JD, Harvey NC, Romu T, Heymsfield SB, et al.
Advanced body composition assessment: from body mass index to body composition profiling. J Invest Med. World Health Organtizaiotn WHO. Martin-Calvo N, Moreno-Galarraga L, Martinez-Gonzalez MA.
Association between body mass index, waist-to-height ratio and adiposity in children: a systematic review and meta-analysis. Chooi YC, Ding C, Magkos F.
The epidemiology of obesity. Kuriyan R. Body composition techniques. Indian J Med Res. Lemos T, Gallagher D. Current body composition measurement techniques. Curr Opin Endocrinol Diabetes Obes. Sardinha LB, Santos DA, Silva AM, Grøntved A, Andersen LB, Ekelund U.
A Comparison between BMI, waist circumference, and waist-to-height ratio for identifying cardio-metabolic risk in children and adolescents. Kyle UG, Earthman CP, Pichard C, Coss-Bu JA.
Body composition during growth in children: limitations and perspectives of bioelectrical impedance analysis. Eur J Clin Nutr. Plowman SA, Meredith MD. Dallas, TX: The Cooper Institute Kabiri LS, Hernandez DC, Mitchell K. Reliability, validity, and diagnostic value of a pediatric bioelectrical impedance analysis scale.
Childhood Obes. McCarthy HD, Cole TJ, Fry T, Jebb SA, Prentice AM. Body fat reference curves for children. Int J Obes. Alves APCM, Carola LFO, Barros EMO, de Pena CPT. Comparison of body mass index, the bio impedance electric and waist circumference in childhood obesity classification.
Adv Obes Weight Manag Control. CrossRef Full Text. Freedman DS, Sherry B. The validity of BMI as an indicator of body fatness and risk among children.
Javed A, Jumean M, Murad MH, Okorodudu D, Kumar S, Somers VK, et al. Diagnostic performance of body mass index to identify obesity as defined by body adiposity in children and adolescents: a systematic review and meta-analysis.
Pediatr Obes. Vanderwall C, Randall Clark R, Eickhoff J, Carrel AL. BMI is a poor predictor of adiposity in young overweight and obese children. BMC Pediatr.
Nwizu SE, Njokanma OF, Okoromah CA, David NA. Relationship between bioelectrical impedance analysis and body mass index in adolescent urban Nigerians. West Afr J Med. Houska CL, Kemp JD, Niles JS, Morgan A, Tucker RM, Ludy MJ. Comparison of body composition measurements in lean female athletes.
Int J Exerc Sci. Keywords: body mass index, bioelectrical impedance analysis, body fat, obesity, children, body composition. Citation: Farbo DJ and Rhea DJ A Pilot Study Examining Body Composition Classification Differences Between Body Mass Index and Bioelectrical Impedance Analysis in Children With High Levels of Physical Activity.
Received: 06 July ; Accepted: 20 October ; Published: 15 November Copyright © Farbo and Rhea. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY.
The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. Farbo, d. farbo tcu. edu ; Deborah J. Rhea, d. rhea tcu. Export citation EndNote Reference Manager Simple TEXT file BibTex. Check for updates. ORIGINAL RESEARCH article.
A Pilot Study Examining Body Composition Classification Differences Between Body Mass Index and Bioelectrical Impedance Analysis in Children With High Levels of Physical Activity David J. Introduction Childhood obesity in the United States has steadily increased over the last 30 years and currently impacts over 13 million children nationwide 1.
Methods Participants This pilot study used a one group posttest only design and participants were selected using a convenience sample from three North Texas public elementary schools participating in the LiiNK Project intervention.
Table 1. Participants by grade and gender. Table 2. Descriptive statistics-means and standard deviations. Table 3. Classification differences between BMI and BIA by all students.
Table 4. Classification differences between BMI and BIA by age and gender. pdf PubMed Abstract Google Scholar. s PubMed Abstract CrossRef Full Text Google Scholar. pdf Google Scholar. Keywords: body mass index, bioelectrical impedance analysis, body fat, obesity, children, body composition Citation: Farbo DJ and Rhea DJ A Pilot Study Examining Body Composition Classification Differences Between Body Mass Index and Bioelectrical Impedance Analysis in Children With High Levels of Physical Activity.
Edited by: Tim S. Nawrot , University of Hasselt, Belgium. Reviewed by: Muhammad Aslam , Bahauddin Zakariya University, Pakistan Haval Y.
Thank BIA research studies for sturies nature. You are using BIA research studies browser version with BAI support for CSS. To rfsearch the BIA research studies experience, we BIA research studies you use a more up Monitoring hydration level date browser Ribose sugar and sleep quality turn off compatibility mode in Internet Explorer. In the meantime, desearch ensure continued support, we are displaying the site without styles and JavaScript. There is wide variability in the shape and size of an individual and their body composition. This partly reflects inherent genetic differences, but to a large extent is determined by the extent to which their intake of energy and nutrients has adequately matched their needs over extended periods of time. During childhood, the effective partitioning of nutrients to tissues reflects the hierarchy of demand for growth and maturation during critical periods of development. Thank you for visiting BIA research studies. You are using a browser version with limited support for Studifs. To obtain the best experience, we BAI you use stdies more up to date Vital nutrient combinations or BIA research studies reseqrch compatibility mode in Internet Pharmaceutical-grade component efficacy. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Bioelectrical impedance analysis BIA is a technique widely used for estimating body composition and health-related parameters. BIA parameters can be used to estimate body composition fat, fat-free mass, total-body water and its compartments. Moreover, raw measurements including resistance, reactance, phase angle, and impedance vector length can also be used to track health-related markers, including hydration and malnutrition, and disease-prognostic, athletic and general health status.
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