Managing And Conducting Phase I And Phase II Clinical Studies

2019 ◽  
pp. 159-174
Author(s):  
John A. Owen
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Clinical Studies ◽  
Conducting Phase

Preclinical and Clinical Pharmacology of Efegatran (LY294468) : A Novel Antithrombin for the Treatment of Acute Coronary Syndromes

1996 ◽  
Vol 2 (4) ◽  
pp. 258-267 ◽  
Author(s):  
Charles V. Jackson ◽  
Julie Satterwhite ◽  
Eiry Roberts
Keyword(s):  
Phase I ◽  
Unstable Angina ◽  
Phase Ii ◽  
Clinical Studies ◽  
Acute Coronary Syndromes ◽  
Anticoagulant Activity ◽  
In Vivo Studies ◽  
Thrombin Time ◽  
Coronary Syndromes ◽  
Dose Dependent

Efegatran (LY294468), a tripeptide arginal in hibitor of the catalytic site of thrombin, is being devel oped as a parenteral anticoagulant for the treatment of acute coronary syndromes. Efegatran was studied in a canine model of coronary artery thrombosis to determine its ability to prevent thrombus formation and as an ad junctive anticoagulant to thrombolysis, in phase I clinical studies, and phase II clinical studies in unstable angina. In the preclinical in vivo studies in dogs, efegatran pro duced a dose-dependent increase in clotting times and demonstrated a selectivity for thrombin time (TT) changes. The activated partial thromboplastin time (APTT)-TT ratio (that is, based on the dose to double each clotting time) determined in dogs from ex vivo blood samples was 8: 1. This observation was similar to that obtained during the phase I studies in normal volunteers where the APTT-TT ratio was 12:1. The canine and hu man clotting systems responded similarly at doses of efe gatran where comparisons could be made (0.25-1.0 mg/ kg/h). The kinetics of the anticoagulant activity of efega tran in dogs and humans were linear and nonsaturable over the dose ranges studied. Efegatran was also found to be an effective adjunctive anticoagulant during streptoki nase-induced thrombolysis in dogs, preventing reocclu sion without increasing bleeding risk. The novel an tithrombin, efegatran, has demonstrated dose-dependent and safe anticoagulation in animal and human studies. Efegatran is presently undergoing phase II clinical studies in unstable angina and acute myocardial infarction pa tients.

Design and results of phase I cancer clinical trials: three-year experience at M.D. Anderson Cancer Center.

1996 ◽  
Vol 14 (1) ◽  
pp. 287-295 ◽  
Author(s):  
T L Smith ◽  
J J Lee ◽  
H M Kantarjian ◽  
S S Legha ◽  
M N Raber
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Alternative Methods ◽  
Recommended Dose ◽  
Cancer Center ◽  
Phase I Trials ◽  
Conducting Phase ◽  
Number Of Patients ◽  
Standard Design ◽  
Baseline Information

PURPOSE Alternatives to the standard design for conducting phase I trials are proposed with increasing frequency. This study was undertaken to determine how phase I trials are currently conducted and to provide a basis for evaluation of evolving methodology. SUBJECTS AND METHODS All published phase I trials from a single institution over a 3-year period were reviewed to determine the method of selection of the recommended dose for a phase II trial of a new agent, type and extent of toxicity, number of patients treated at the recommended dose, and clinical response. RESULTS All 23 published trials used the standard method of entering cohorts of patients at increasing dose levels and observing toxic effects to determine the dose recommended for phase II study. Among 610 patients, 26% were treated at or within 10% of the recommended dose and 35% were treated with less than 50% of the recommended dose or on a trial that yielded no recommended dose. Among 18 trials using agents previously tested in humans, fewer patients were treated at much less than the recommended dose. For trials in which myelosuppression was dose-limiting, the estimated probability of serious myelosuppression associated with the recommended dose ranged from 23% to 66%. Nineteen patients (3%) responded to therapy. CONCLUSION This summary of phase I trials recently conducted at M.D. Anderson Cancer Center confirms the need for alternative methods, provides baseline information against which alternatively conducted trials can be compared, and demonstrates some practical clinical trial issues not generally considered when alternative methods are proposed.

Bewegungstherapie und körperliche Aktivität bei Patienten mit Herzinsuffizienz

Praxis ◽  
2018 ◽  
Vol 107 (17-18) ◽  
pp. 951-958 ◽  
Author(s):  
Matthias Wilhelm
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Körperliche Aktivität ◽  
Phase Iii

Zusammenfassung. Herzinsuffizienz ist ein klinisches Syndrom mit unterschiedlichen Ätiologien und Phänotypen. Die überwachte Bewegungstherapie und individuelle körperliche Aktivität ist bei allen Formen eine Klasse-IA-Empfehlung in aktuellen Leitlinien. Eine Bewegungstherapie kann unmittelbar nach Stabilisierung einer akuten Herzinsuffizienz im Spital begonnen werden (Phase I). Sie kann nach Entlassung in einem stationären oder ambulanten Präventions- und Rehabilitationsprogramm fortgesetzt werden (Phase II). Typische Elemente sind Ausdauer-, Kraft- und Atemtraining. Die Kosten werden von der Krankenversicherung für drei bis sechs Monate übernommen. In erfahrenen Zentren können auch Patienten mit implantierten Defibrillatoren oder linksventrikulären Unterstützungssystemen trainieren. Wichtiges Ziel der Phase II ist neben muskulärer Rekonditionierung auch die Steigerung der Gesundheitskompetenz, um die Langzeit-Adhärenz bezüglich körperlicher Aktivität zu verbessern. In Phase III bieten Herzgruppen Unterstützung.

How to Make COVID-19 Contact Tracing Apps work: Insights from Behavioral Economics (Preprint)

2021 ◽  
Author(s):  
Ian Ayres ◽  
Alessandro Romano ◽  
Chiara Sotis
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Network Effects ◽  
Risky Behaviors ◽  
Contact Tracing ◽  
Risk Compensation ◽  
Main Function ◽  
Double Blind ◽  
Compensation Theory ◽  
Pros And Cons

BACKGROUND Due to network effects, Contact Tracing Apps (CTAs) are only effective if many people download them. However, the response to CTAs has been tepid. For example, in France less than 2 million people (roughly 3% of the population) downloaded the CTA. Consequently, CTAs need to be fundamentally rethought to increase their effectiveness. OBJECTIVE This study aimed to show that CTAs can still play a key role in containing the pandemic, provided that they take into account insights from behavioral sciences. Moreover, we study whether emphasizing the virtues of CTA to induce people to download them makes app users engage in more risky behaviors (risk compensation theory) and whether feedback on a user’s behavior affects future behaviors. METHODS We perform a double-blind online experiment (n=1500) divided in two phases. In Phase I respondents are randomly assigned to one of three different groups: Pros of the app, Pros and Cons of the app and Control I. Respondents in the Pros group were shown information on the advantages of CTAs. Participants in the Pros and Cons group were shown information on both the advantages and the problems that characterize CTAs. Last, respondents in the Control I group were not given any information on CTAs. All participants are then asked how worried they are about the pandemic, how likely they are to download the app, and on how they intend to behave (e.g. attend small and large gathering, wear a mask, etc.). A week later we carried out Phase II. Participants in Phase II were randomly assigned to different in-app notifications in which they were informed on how much risk they were taking compared to the average user. We then ask participants their intentions for future behaviors to investigate whether these notifications were effective in making respondents more prudent. RESULTS All 1500 participants completed phase I of the experiment, whereas 1303 (86.9%) completed also phase 2. The main findings are: i) informing people on the pros of the app make them less worried about the pandemic (p=.004), ii) informing people about both the pros and the cons of the app makes them more likely to download the app (p=.07); iii) carefully devised in-app notification induce people to state that they will: attend less large gatherings (p= .05) and less small gatherings (p= .001), see less people at risk (p=.004), that they stay more at home (p=.006) and wear more often the mask (p=.09). We do not find support for the risk-compensation theory. CONCLUSIONS we suggest that CTAs should be re-framed as Behavioral Feedback Apps (BFAs). The main function of BFAs would be providing users with information on how to minimize the risk of contracting COVID-19, e.g. to provide information on how crowded a store is likely to be at a given time of the day. Moreover, the BFA could have a rating system that allows users to flag stores that do not respect safety norms, such as mandating customers to wear a mask or not respecting social distancing. These functions can inform the behavior of app users, thus playing a key role in containing the spread of the virus even if a small percentage of people download the BFA. While effective contact tracing is impossible when only 3% of the population downloads the app, less risk taking by small portions of the population can produce large benefits. BFAs can be programmed so that users can also activate a tracing function akin to the one currently carried out by CTAs. Making contact tracing an ancillary, opt-in function might facilitate a wider acceptance of BFAs.

scholarly journals Analysis of the ex-vivo transformation of semen, saliva and urine as they dry out using ATR-FTIR spectroscopy and chemometric approach

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tanurup Das ◽  
Abhimanyu Harshey ◽  
Ankit Srivastava ◽  
Kriti Nigam ◽  
Vijay Kumar Yadav ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Ex Vivo ◽  
Body Fluids ◽  
Biochemical Changes ◽  
Partial Least Square ◽  
The Body ◽  
Slow Phase ◽  
Time Since Deposition ◽  
Dry Out

AbstractThe ex-vivo biochemical changes of different body fluids also referred as aging of fluids are potential marker for the estimation of Time since deposition. Infrared spectroscopy has great potential to reveal the biochemical changes in these fluids as previously reported by several researchers. The present study is focused to analyze the spectral changes in the ATR-FTIR spectra of three body fluids, commonly encountered in violent crimes i.e., semen, saliva, and urine as they dry out. The whole analytical timeline is divided into relatively slow phase I due to the major contribution of water and faster Phase II due to significant evaporation of water. Two spectral regions i.e., 3200–3400 cm−1 and 1600–1000 cm−1 are the major contributors to the spectra of these fluids. Several peaks in the spectral region between 1600 and 1000 cm−1 showed highly significant regression equation with a higher coefficient of determination values in Phase II in contrary to the slow passing Phase I. Principal component and Partial Least Square Regression analysis are the two chemometric tool used to estimate the time since deposition of the aforesaid fluids as they dry out. Additionally, this study potentially estimates the time since deposition of an offense from the aging of the body fluids at the early stages after its occurrence as well as works as the precursor for further studies on an extended timeframe.

scholarly journals Detoxification of the tricyclic antidepressant opipramol and its analog – IS-noh by UGT enzymes before and after activation by phase I enzymes in rat liver microsomes

2021 ◽  
Author(s):  
Anna Mieszkowska ◽  
Koleta Hemine ◽  
Anna Skwierawska ◽  
Ewa Augustin ◽  
Zofia Mazerska
Keyword(s):  
Phase I ◽  
Rat Liver ◽  
Phase Ii ◽  
Oxidation Product ◽  
Liver Microsomes ◽  
Correct Selection ◽  
Rat Liver Microsomes ◽  
Recombinant Enzymes ◽  
Data Set ◽  
Phase I Enzymes

AbstractThe present studies were carried out to evaluate the simultaneous one-pot metabolism of opipramol (IS-opi) and analog (IS-noh) by phase I and phase II enzymes present in rat liver microsomes (RLM) as an alternative to separate testing with recombinant enzymes. This approach allows for more time-saving and cost-effective screening of the metabolism of newly discovered drugs. We also considered that the lack of results for phase II, including UGT, often creates problems in correct selection of valuable compounds. Moreover, microsomes data set is richer in the contest and provides medical scientist to determine also the susceptibility of drugs to undergo phase I and then phase II. In the present work, we have shown that IS-noh was metabolized in vitro by phase I enzymes to the oxidation product, which was next transformed with UGTs to glucuronide. The results showed also that the previously known oxidation product of opipramol was changed to previously no reported glucuronidation product by UDP-glucuronosyltransferases. In addition, unlike IS-noh, opipramol did not prove to be the substrate for UGTs. Therefore, tricyclic antidepressants depending on the structure can trigger a different response after contact with UGT enzymes. Some will metabolize directly with UGTs, others only after activation by phase I enzymes.

scholarly journals Nurses’ educational needs when dealing with aggression from patients and their families: a mixed-methods study

BMJ Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. e041711
Author(s):  
Kana Sato ◽  
Yoshimi Kodama
Keyword(s):  
Mixed Methods ◽  
Nursing Students ◽  
Phase I ◽  
Phase Ii ◽  
Mixed Methods Study ◽  
Self Awareness ◽  
Two Phase ◽  
Sequential Mixed Methods ◽  
Nursing Professionals ◽  
Educational Contents

ObjectivesTo explore the type of education needed for nurses when dealing with aggression from patients and their families.DesignA two-phase sequential mixed-methods study.SettingThis study was conducted in Japan, with phase I from March to November 2016 and phase II in November 2018.Main outcome measuresThe challenges faced by nurses when dealing with incidents of aggression from the neutral perspective of neither nurse nor patient/family and perceptions of the educational contents developed in this study. Descriptive analyses were used to examine the data retrieved from both phases.ParticipantsPhase I entailed semistructured interviews among 11 neutral-party participants who observed aggressive incidents between nurses and patients/families. Phase II consisted of a web survey conducted among 102 nursing students and 308 nursing professionals.ResultsPhase I resulted in the identification of the following five main educational components: understanding the mechanisms of anger and aggression, maintaining self-awareness, observant listening, managing the self-impression, and communicating based on specific disease characteristics. Each component was related to improved communication through self-awareness. The results of phase II indicated that participants positively perceived these educational contents as likely to be effective for dealing with aggression from patients/families.ConclusionsThis study clarified the type of education needed for nurses when dealing with aggression based on multiple viewpoints. Specifically, neutral-party interviews revealed that communication should be improved through self-awareness. A subsequent survey among nurses and nursing students showed that the identified educational contents were positively received.

Role of Phase II Enzymes in the Bioactivation of 1,4-Dichlorobenzene and 1,4-Dibromobenzene

1996 ◽  
Vol 24 (4) ◽  
pp. 603-608
Author(s):  
Moreno Paolini ◽  
Laura Pozzetti ◽  
Renata Mesirca ◽  
Andrea Sapone ◽  
Paola Silingardi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Phase I ◽  
Phase Ii ◽  
Covalent Binding ◽  
Fold Increase ◽  
Test System ◽  
Oxidative Enzymes ◽  
Transferase Activity ◽  
Genetic Toxicology

The use of sodium phenobarbital (PB, CYP2B1 inducer) combined with β-naphthoflavone (β-NF, 1A1) to induce certain Phase I reactions in S9 liver fractions is a standard method for conducting short-term bioassays for genotoxicity. However, because post-oxidative enzymes are also able to activate many precarcinogens, we tested the possibility of adapting S9 liver fractions derived from Phase II-induced rodents to the field of genetic toxicology. In this study, S9 liver fractions derived from Swiss albino CD1 mice fed 7.5g/kg 2-(3)-tert-butyl-4-hydroxyanisole (BHA; a monofunctional Phase II-inducer) for 3 weeks, show a clear pattern of induction with an approximately 3.5–9.5-fold increase in glutathione S-transferase activity. In vitro DNA binding of the promutagenic agents, [14C]-l,4-dichlorobenzene (DCB) and [14C]-1,4-dibromobenzene (DBB), is mediated by such metabolic liver preparations and showed a significant increase in covalent binding capability. In some instances, enzyme activity was more elevated when compared to that obtained with traditional (Phase I-induced) S9. Together with DNA binding, the genetic response of these chemicals in the diploid D7 strain of Saccharomyces cerevisiae used as a biological test system, revealed the ability of the BHA-derived preparations to activate the promutagenic agents, as exemplified by the significant enhancement of mitotic gene-conversion (up to 5.2-fold for DCB and 3.4-fold for DBB) and reverse point mutation (up to 3.6-fold for DCB and 2.5-fold for DBB) at a 4mM concentration. This novel metabolising biosystem, with enhanced Phase II activity, is recommended together with a traditional S9, for detecting unknown promutagens in genotoxicity studies. The routine use of either oxidative or post-oxidative S9 increases the responsiveness of the test and can contribute to the identification of promutagens not detected when using traditional protocols.

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