scholarly journals Historical Perspective on Clinical Trials of Carnitine in Children and Adults

2016 ◽  
Vol 68 (Suppl. 3) ◽  
pp. 1-4 ◽  
Author(s):  
Neil R.M. Buist
Keyword(s):  
Clinical Trials ◽  
Inborn Errors Of Metabolism ◽  
Randomized Clinical Trials ◽  
Ethical Issues ◽  
Carnitine Deficiency ◽  
Nutritional Deficiencies ◽  
Inborn Errors ◽  
Treatment Protocols ◽  
The Us ◽  
Primary Carnitine Deficiency

The metabolic roles of carnitine have been greatly clarified over the past 50 years, and it is now well established that carnitine is a key player in mitochondrial generation of energy and metabolism of acetyl coenzyme A. A therapeutic role for carnitine in treatment of nutritional deficiencies in infants and children was first demonstrated in 1958, and since that time it has been used to treat a number of inborn errors of metabolism. Carnitine was approved by the US Food and Drug Administration in 1985 for treatment of ‘primary carnitine deficiency', and later in 1992 for treatment of ‘secondary carnitine deficiency', a definition that included the majority of relevant metabolic disorders associated with low or abnormal plasma carnitine levels. Today, carnitine treatment of inborn errors of metabolism is a safe and integral part of many treatment protocols, and a growing interest in carnitine has resulted in greater recognition of many causes of carnitine depletion. Notwithstanding, there is still a lack of data from randomized clinical trials, even on the use of carnitine in inborn errors of metabolism, although ethical issues may be a contributing factor in this regard.

scholarly journals Sickle Cell Disease Patients Demonstrate a High Willingness to Participate in Randomized Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5808-5808
Author(s):  
Volha Mazziotto ◽  
Katrina Mikofalvy ◽  
Alexandra Houck ◽  
Lauren Beck ◽  
Prasad V. Bodas
Keyword(s):  
Clinical Trials ◽  
African American ◽  
African Americans ◽  
Randomized Clinical Trials ◽  
Willingness To Participate ◽  
Participation Rates ◽  
Cell Disease ◽  
African American Population ◽  
The Us ◽  
Reported Data

Abstract Background: African Americans are underrepresented in randomized clinical trials (RCTs). Underrepresentation of this patient group may lead to an inadequate analysis of therapy risks and benefits, and study findings may not be generalizable to a diverse patient population. Moreover, low representation of African Americans in existing clinical trials may discourage future trials focused on this population, as such trials are perceived to be infeasible. Barriers to participation in clinical trials have been extensively studied. Frequently identified factors include: systemic barriers (availability of clinical trials, eligibility barriers, lack of resources), geography (location of the research institution and access to transportation), and individual-level barriers such as low education, poverty, and poor access to healthcare. Willingness to participate has been cited as a major barrier, related to distrust in the US healthcare systemand to cultural and religious beliefs. Yet a dearth of empirical evidence bolsters the assertion that willingness to participate in clinical trials among African Americans is accountable for underrepresentation. We performed a retrospective review of major RCTs focused on sickle cell disease (SCD) in order to measure willingness of African Americans to participate in clinical research. Methods: We systematically identified landmark peer-reviewed RCTs focused on SCD. We analyzed the results of these trials reported in the medical literature and calculated participation and completion rates for each trial. For each study, we identified the number of subjects screened for participation, the number who agreed to participate, and the number who declined. We calculated ratios for study acceptance and study completion. We identified the number of publications which clearly reported data from which acceptance to participate could be directly calculated, the number from which participation could be inferred, or from which reported data were insufficient. Results: We identified 13 RCTs published between 1986 and 2018, representing the major clinically impactful studies in children and adults with SCD. Six of the 13 studies reported sufficient data to infer or calculate participation rates. It is notable that more than half (54%; n=7) of the studies provided insufficient data to calculate study acceptance rates. Our analysis encompassing 2407 patients included in six studies indicates that 82% of subjects with SCD demonstrated willingness to participate in an RCT (range 32-94%), and 95% of clinical trial subjects completed study activities (range 92-98%). Discussion: A minority of publications reported participation data. One of the 13 studies published data on the race of participants, reporting 94% of participants were African American and 3% were Hispanic. However, since SCD predominantly affects African Americans (approximately 90% of those with SCD nationwide are African American and approximately 10% are Hispanic), it is reasonable to estimate that the subjects in our analysis represent a predominantly African American population. We acknowledge that subjects with SCD may not be representative of the US African American population in total. Nonetheless, our findings contradict the assertion that African Americans are less willing to participate in clinical trials, or that African Americans have disproportionately high drop-out rates. Only a minority of publications reported data required to calculate participation rates. Despite this limitation, available empiric evidence suggests that when participation in high-quality clinical trials is made available, African Americans demonstrate a willingness and capacity to enroll and complete study participation. The generalized assertion that African American patients' willingness to participate in research is a major factor in their underrepresentation in clinical trials is false. Researchers should design high-quality clinical trials that include this underrepresented group at the outset, and investigators should be encouraged to collect and report participation data more carefully so that this disparity can be measured and addressed. Disclosures No relevant conflicts of interest to declare.

Recommendations for Clinical Trials of Off-Label Drugs Used to Treat Advanced-Stage Cancer

2012 ◽  
Vol 30 (6) ◽  
pp. 661-666 ◽  
Author(s):  
C. Daniel Mullins ◽  
Russ Montgomery ◽  
Amy P. Abernethy ◽  
Arif Hussain ◽  
Steven D. Pearson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Administration ◽  
Randomized Clinical Trials ◽  
Technology Policy ◽  
Food And Drug Administration ◽  
Decision Makers ◽  
Public And Private ◽  
Off Label ◽  
The Us ◽  
Before And After

Purpose To provide recommendations to trialists and sponsors that guide the design and implementation of prospective postapproval clinical trials for oncology drugs used outside US Food and Drug Administration–labeled indications for treatment of late-stage cancers. Methods A meeting was hosted by the Center for Medical Technology Policy in Baltimore, MD, on November 12, 2009. Discussions during the meeting and key informant interviews were conducted before and after this stakeholder meeting. Peer review by multidisciplinary stakeholders was followed by a public comment period. Input was received from patient advocacy groups, medical oncologists, pharmaceutical companies, the US Food and Drug Administration, Centers for Medicare and Medicaid Services, the National Cancer Institute, foreign government agencies involved in health technology assessment, public and private payers, drug compendia, clinical research entities, statisticians, academics, and the American Society of Clinical Oncology. Results To address the needs of patients and their clinical providers, compendia, payers, and policy makers, recommendations are proposed to guide the design of future prospective trials for off-label use of oncology drugs across four areas: trial design and data analysis, patient and site recruitment, comparators, and outcomes. Conclusion The US Food and Drug Administration provides guidance to the pharmaceutical industry and others designing randomized clinical trials for regulatory approval. However, a gap exists for postregulatory decision makers, including patients, prescribers, and payers, because regulatory trials do not answer the questions most relevant to them. Therefore, guidance is needed for trials performed in the postapproval environment for these postapproval decision makers.

Use of Nonhuman Milks in the Dietary Management of Young Children With Acute Diarrhea: A Meta-Analysis of Clinical Trials

PEDIATRICS ◽  
1994 ◽  
Vol 93 (1) ◽  
pp. 17-27
Author(s):  
Kenneth H. Brown ◽  
Janet M. Peerson ◽  
Olivier Fontaine
Keyword(s):  
Clinical Trials ◽  
Young Children ◽  
Treatment Failure ◽  
Acute Diarrhea ◽  
Randomized Clinical Trials ◽  
World Health ◽  
Milk Formula ◽  
Failure Rates ◽  
Treatment Protocols ◽  
Oral Rehydration

Objective. To assess the effects of continued feeding of nonhuman milks or formulas to young children during acute diarrhea on their treatment failure rates, stool frequency and amount, diarrheal duration, and change in body weight. Methods. A total of 29 randomized clinical trials of 2215 patients were identified by computerized bibliographic search and review of published articles. Data were abstracted and analyzed using standard meta-analytic procedures. Results. Among studies that compared lactose-containing milk or formula diets with lactose-free regimens, those children who received the lactose-containing diets during acute diarrhea were twice as likely to have a treatment failure as those who received a lactose-free diet (22% vs 12%, respectively; P < .001). However, the excess treatment failure rates occurred only in those studies that included patients whose initial degree of dehydration, as reported by authors, was severe, or that were conducted before 1985, when appropriate diarrhea treatment protocols were first widely accepted. Among studies of patients with mild diarrhea, all but one of which were completed after 1985, the overall treatment failure rates in the lactose groups were similar to the rates in the lactose-free groups (13% vs 15%). These results suggest that children with mild or no dehydration and those who are managed according to appropriate treatment protocols, such as that promoted by the World Health Organization, can be treated as successfully with lactose-containing diets as with lactose-free ones. The pooled information from studies that compared undiluted lactose-containing milks with the same milks offered at reduced concentration concluded that (1) children who received undiluted milks were marginally more likely to experience treatment failure than those who received diluted milk (16% vs 12%, P = .05), (2) the differences in stool output were small and of limited clinical importance, and (3) children who received the undiluted milk diets gained 0.25 SD more weight than those who received the diluted ones (P = .004). In addition, as with the previous set of studies, there were no differences in the pooled treatment failure rates between the respective groups in those studies of mildly dehydrated patients conducted after 1985 (14% vs 12%). Conclusions. The vast majority of young children with acute diarrhea can be successfully managed with continued feeding of undiluted nonhuman milks. Routine dilution of milk and routine use of lactose-free milk formula are therefore not necessary, especially when oral rehydration therapy and early feeding (in addition to milk) form the basic approach to the clinical management of diarrhea in infants and children.

The Role of L-Carnitine in Pediatric Cardiomyopathy

1995 ◽  
Vol 10 (2_suppl) ◽  
pp. 2S45-2S51 ◽  
Author(s):  
Susan Winter ◽  
Kenneth Jue ◽  
James Prochazka ◽  
Paul Francis ◽  
Wade Hamilton ◽  
...  
Keyword(s):  
Energy Production ◽  
Inborn Errors Of Metabolism ◽  
Genetic Factors ◽  
Myocardial Dysfunction ◽  
Essential Element ◽  
Carnitine Deficiency ◽  
Inborn Errors ◽  
Pediatric Cardiomyopathy ◽  
Traditional Therapies

Metabolic and genetic factors underlie some forms of cardiomyopathy in childhood. A variety of inborn errors of metabolism can impair mitochondrial energy production, or β-oxidation, in the heart and lead to myocardial dysfunction. L-Carnitine, an essential element of β-oxidation, transports fatty acids across the mitochondrial membrane for energy production. L-Carnitine deficiency syndromes are now well described as secondary to a variety of inborn errors of metabolism and often include cardiomyopathy in the clinical picture. Despite traditional therapies for cardiomyopathy, mortality for this disorder remains at well over 50%. Review of reports of L-carnitine supplementation studies and results from our own trial underscore the importance of its role in cardiac function and demonstrates that there is likely a subpopulation of patients with cardiomyopathy responsive to L-carnitine treatment. (J Child Neurol 1995; 10(Suppl):2S45-2S5 1).

scholarly journals How to continue COVID-19 vaccine clinical trials? The ethics of vaccine research in a time of pandemic

2021 ◽  
pp. 147775092110524
Author(s):  
Silvia Ceruti ◽  
Marco Cosentino ◽  
Mario Picozzi
Keyword(s):  
Clinical Trials ◽  
Ethical Issues ◽  
Vaccination Campaign ◽  
Scientific Information ◽  
Well Being ◽  
Resource Scarcity ◽  
European Medicines Agency ◽  
Human Beings ◽  
Controlled Clinical Trials ◽  
The Us

Between December 2020 and March 2021, the US Food and Drug Administration and the European Medicines Agency issued Emergency Use Authorizations and Conditional Marketing Authorizations for the distribution of the first COVID-19 vaccines. Although these vaccines were thoroughly assessed before their approval, regulators required companies to continue ongoing placebo-controlled clinical trials in order to gather further reliable scientific information on their safety and efficacy, as well as to start new studies to evaluate additional candidates. The aim of this paper is to present and discuss the ethical issues raised by the tension between the need to continue these types of clinical trials and the obligations related to the protection of the rights and well-being of research participants. Specifically, we question whether—how, and to what extent—fundamental principles governing research involving human beings can be applied to the current pandemic situation. We argue that continuing ongoing placebo-controlled clinical trials can be considered ethically justifiable only if all participants are adequately informed of any developments that may affect their willingness to remain enrolled, including the current situation of resource scarcity and the prioritization criteria established for vaccination. However, we also argue that currently approved vaccines, which are considered safe and effective enough to be administered to millions of people as part of the vaccination campaign, necessarily represent the “best proven intervention” currently available and, therefore, should be used as comparators in future studies instead of placebo.

Ethical issues in adult oncology randomized clinical trials

2011 ◽  
Vol 1 (5) ◽  
pp. 629-636 ◽  
Author(s):  
Erika P Hamilton ◽  
Jeffrey M Peppercorn
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Ethical Issues

scholarly journals Omega 3 fatty acids and inborn errors of metabolism

2012 ◽  
Vol 107 (S2) ◽  
pp. S129-S136 ◽  
Author(s):  
Mercedes Gil-Campos ◽  
Pablo Sanjurjo Crespo
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Inborn Errors Of Metabolism ◽  
Scientific Evidence ◽  
Nutritional Deficiencies ◽  
Neural Function ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Inborn Errors ◽  
Double Blind

A number of studies are investigating the role of n-3 polyunsaturated fatty acids in children with metabolic inborn errors, while the effects on visual and brain development in premature infants and neonates are well known. However, their function incertain chronic neurological, inflammatory and metabolic disorders is still under study. Standards should be established to help identify the need of docosahexaenoic acid supplementation in conditions requiring a restricted diet resulting in an altered metabolism system, and find scientific evidence on the effects of such supplementation. This study reviews relevant published literature to propose adequate n-3 intake or supplementation doses for different ages and pathologies. The aim of this review is to examine the effects of long chain polyunsaturated fatty acids supplementation in preventing cognitive impairment or in retarding its progress, and to identify nutritional deficiencies, in children with inborn errors of metabolism. Trials were identified from a search of the Cochrane and MEDLINE databases in 2011. These databases include all major completed and ongoing double-blind, placebo-controlled, randomized trials, as well as all studies in which omega-3 supplementation was administered to children with inborn errors, and studies assessing omega-3 fatty acids status in plasma in these pathologies. Although few randomized controlled trials met the inclusion criteria of this review, some evidenced that most of children with inborn errors are deficient in omega-3 fatty acids, and demonstrated that supplementation might improve their neural function, or prevent the progression of neurological impairment. Nontheless, further investigations are needed on this issue.

scholarly journals Carnitine Inborn Errors of Metabolism

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3251 ◽  
Author(s):  
Mohammed Almannai ◽  
Majid Alfadhel ◽  
Ayman W. El-Hattab
Keyword(s):  
Inborn Errors Of Metabolism ◽  
Treatment Options ◽  
Carnitine Deficiency ◽  
Carnitine Palmitoyltransferase ◽  
Inborn Errors ◽  
Carnitine Transporter ◽  
Carnitine Metabolism ◽  
Carnitine Transport ◽  
Cpt I ◽  
Carnitine Palmitoyltransferase Ii

Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine–acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine–acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency.

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