Ignite Creation Date:
2024-05-05 @ 5:06 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00386386
Status:
COMPLETED
Last Update Posted:
2008-03-13
First Post:
2006-10-06
Brief Title:
Recombinant Hyaluronidase in Out-of-Hospital Setting The EASI Access Trial
Sponsor:
Massachusetts General Hospital
Organization:
Massachusetts General Hospital
Study Overview
Official Title:
Enzymatically Augmented Subcutaneous Infusion EASI In Out-Of-Hospital Care
Status:
COMPLETED
Status Verified Date:
2008-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The studys overarching aim is to determine whether Enzymatically Augmented Subcutaneous Infusion EASI can assist in out-of-hospital situations characterized by mismatch between need for and ability to achieve access to the vascular compartment One mechanism for providing access to the vascular compartment subcutaneous infusion is facilitated by administration of hyaluronidase the hyaluronidase hydrolyzes hyaluronan the major subcutaneous diffusion barrier Hyaluronidase thus increases local dispersion and absorption of subcutaneously administered drugs and fluids
The EASI Access study is intended to be the first out-of-hospital study assessing FDA-approved Chinese hamster ovary-derived recombinant hyaluronidase the recombinant product is hereafter referred to by the shorter brand name Hylenex The EASI Access will test some fundamental principles and will facilitate design and implementation of follow-up investigations eg extension of access to non-ALS providers For example we will attempt to show that EASI access is simple effective and has few or no downsides as compared to IV access
The EASI Access study is intended to be the first out-of-hospital study assessing FDA-approved Chinese hamster ovary-derived recombinant hyaluronidase the recombinant product is hereafter referred to by the shorter brand name Hylenex The EASI Access will test some fundamental principles and will facilitate design and implementation of follow-up investigations eg extension of access to non-ALS providers For example we will attempt to show that EASI access is simple effective and has few or no downsides as compared to IV access
Detailed Description:
Background Challenges to IV access outside the hospital The out-of-hospital setting can pose myriad challenges to the provider attempting to gain access to the intravascular compartment In an individual patient encounter placement of an intravenous IV catheter may be hampered by anatomy eg venous collapse in hypotension positioning eg entrapment and environmental conditions such as lighting and vehicular motion These problems may be compounded in situations where multiple patients simultaneously require expedited IV access Therefore both host ie patient and environment ie physical setting parameters can contribute to a mismatch between desire for and ability to achieve access to the intravascular compartment
The aforementioned issues with IV line placement all make the assumption of presence of an operator with appropriate Advanced Life Support ALS-level training and credentials Such may not be the case in a mass casualty incident MCI situation or in a situation where initial responders are Basic Life Support BLS level Thus consideration of potential barriers to intravascular compartment access should include personnel as well as host and environment parameters
Case for importance of access to intravascular compartment Is intravascular access really important Assuming that an EMS system could fiat easy and widespread access to the intravascular compartment in an MCI or more routine ALS or BLS response is there impact on outcome Unfortunately as is often the case with EMS interventions there is little or no randomized controlled evidence addressing the issue - in fact related literature on penetrating trauma suggests that prehospital fluid resuscitation may be deleterious However clinical practice as well as standard emergency medicine and trauma resuscitation teaching such as the Advanced Cardiac Life Support course and the Advanced Trauma Life Support text do emphasize importance of early fluid resuscitation for a variety of injuries and illnesses1 In addition literature addressing MCI situations eg crush injuries makes a strong case for the importance of fluid replacement2 Besides opening an avenue for fluid replacement catheter-based access to the intravascular compartment allows for reliable delivery of medications For patients who are not tolerating po intake or for those who otherwise stand to benefit from parenteral drug delivery catheter-based access to the intravascular compartment allows for administration of repeated doses of a variety of drugs while avoiding multiple often painful injections Once the catheter is placed currently in a vein the access line is available to both initial and subsequent caregivers
It is obvious that out-of-hospital caregivers may use the access line for administration of drugs in the limited prehospital pharmacopoeia but it is equally true that pre-establishment of intravascular access saves a step on arrival to the next level of care Practitioners in todays EDs currently benefit in savings of nursing time from not having to take time to establish IV access in patients transported to the hospital by ALS units This helps both the individual patient with pre-established IV access since ED staff can immediately administer time-critical drugs - including those not in the ALS armamentarium - and also aids the resource-taxed ED whose staff can execute duties other than starting IV lines Furthermore though there is no concrete supporting evidence common wisdom holds that placement of a smaller IV line and fluid administration through that line may facilitate subsequent placement of a larger IV line due to more fluid in the vascular compartment
Thus the balance of evidence from a variety of standpoints outcomes research accepted practice and teaching logistics supports an argument that ability to gain access to the intravascular compartment is an important priority for out-of-hospital care Importantly it should be noted that for ED one could substitute triage tent or other MCI-related care site since intravascular compartment access is of obvious import in MCIdisaster-type situations
Potential role for EASI Mechanism of subcutaneous infusion Subcutaneously administered drugs and infusates must traverse an interstitial matrix to enter the vascular or lymphatic system The interstitiums resistance to drug permeation can be envisioned as functioning like a three-dimensional filter through which drugsinfusates must pass There are large molecules such as elastin and collagen inhabiting a matrix of hydrated gel-like glycosaminoglycans and proteoglycans Among the glycosaminoglycans is hyaluronan which contributes to the resistance of fluid flow through the interstitium Though hyaluronan is found in lower concentration than collagen in the skin it plays a disproportionately large role in resisting fluid movement3 Hyaluronidase modifies connective tissue permeability via hydrolyzing hyaluronic acid effecting a cleavage of the glucosaminidic bond between N-acetylglucosamine and glucuronic acid moieties The cleavage results in a decrease in viscosity of the cellular cement and promotes diffusion of injected fluids facilitating their absorption The decrease in viscosity is reversed within 24 hours due to the rapid inactivation of the hyaluronidase enzyme and also due to the rapid turnover rate of skin hyaluronan4 5 So-called spreading agents historically derived from animal extracts have been used clinically to facilitate dispersion and absorption of other drugs for over 50 years4 The extensive history of spreading agent use was relevant to the FDA review of the new recombinant enzyme Based in part upon the longtime uses of nonrecombinant hyaluronidase the FDA approval for Hylenex states the drug is Indicated as an adjuvant to increase the absorption and dispersion of other injected drugs for hypodermoclysis and as an adjunct in subcutaneous urography for improving resorption of radiopaque agents Subcutaneous infusion instead of or prior to IV infusion
Out-of-hospital clinical scenarios vary widely It is certainly true that not all EMS patients or MCI patients need an IV line However it is easy to think of out-of-hospital situations in which rapidly and easily placed intravascular access could be very helpful and in which standard IV catheters may not be the sole solution To name but a few examples there could be a
Single-patient encounter where the IV line is difficult to place
Multi-car motor vehicle crash MVC site attended by many BLS but few ALS providers
Marathon medical support tent confronted with scores of volume-depleted individuals
Building collapse eg in an earthquake with numerous victims in whom simultaneous and timely fluid replacement can stave off crush-mediated renal failure Standard texts such as the American College of Surgeons Advanced Trauma Life Support note that the need for IV access is often present in cases where there is no ability to place an indwelling vascular catheter The ATLS text points out that fluid resuscitation in clinically challenging environments eg austere conditions MCI situations is often of sufficient criticality that in the absence of IV access hydration should be attempted through oral or rectal routes As the ACS Committee on Trauma writes oral hydration has obvious aspiration and absorption risks and rectal clysis as it is denoted in the ATLS text presents obvious logistic and patient comfort issues in the field1 It is thus clear that there is a potential role for EASI access if such access extends the ability to usefully reach the intravascular compartment In terms of its potential as a mechanism for out-of-hospital fluid replacement and as a route for drug administration EASI warrants attention in the form of a trial
Compared to the current standard of IV and perhaps intraosseous line placement by ALS-level providers EASI access could enable out-of-hospital responders ALS as well as lower echelon providers to achieve intravascular access in more patients more quickly more reliably and with less pain We thus plan to conduct the EASI Access study for out-of-hospital providers as a mechanism to investigate whether EASI access can accrue the hypothesized advantages The study will begin with ALS-level providers The ultimate plan should ALS provider EASI prove efficient will be to assess whether simple placement of EASI access by non-ALS providers can extend the reach of advanced care providers in situations where need for IV access outstrips available resources
Not specifically the goal of the EASI Access trial but potentially relevant for any future use of Hylenex is that the ability to avoid IV access may be occasionally useful in the acute care setting In patients who are very young or cachectic or simply need IV access for fluid replacement EASI may be able to obviate the need for possibly numerous IV sticks and their attendant discomfort The low but nonzero rate of IV access complications eg thrombosis phlebitis in general may also be avoided by use of EASI access The EASI Access investigation very clearly does not offer these potential advantages to the current trials study subjects but the hypothetical advantages to avoiding IV placement do provide further possible relevance to any positive findings in the EASI Access study
The aforementioned issues with IV line placement all make the assumption of presence of an operator with appropriate Advanced Life Support ALS-level training and credentials Such may not be the case in a mass casualty incident MCI situation or in a situation where initial responders are Basic Life Support BLS level Thus consideration of potential barriers to intravascular compartment access should include personnel as well as host and environment parameters
Case for importance of access to intravascular compartment Is intravascular access really important Assuming that an EMS system could fiat easy and widespread access to the intravascular compartment in an MCI or more routine ALS or BLS response is there impact on outcome Unfortunately as is often the case with EMS interventions there is little or no randomized controlled evidence addressing the issue - in fact related literature on penetrating trauma suggests that prehospital fluid resuscitation may be deleterious However clinical practice as well as standard emergency medicine and trauma resuscitation teaching such as the Advanced Cardiac Life Support course and the Advanced Trauma Life Support text do emphasize importance of early fluid resuscitation for a variety of injuries and illnesses1 In addition literature addressing MCI situations eg crush injuries makes a strong case for the importance of fluid replacement2 Besides opening an avenue for fluid replacement catheter-based access to the intravascular compartment allows for reliable delivery of medications For patients who are not tolerating po intake or for those who otherwise stand to benefit from parenteral drug delivery catheter-based access to the intravascular compartment allows for administration of repeated doses of a variety of drugs while avoiding multiple often painful injections Once the catheter is placed currently in a vein the access line is available to both initial and subsequent caregivers
It is obvious that out-of-hospital caregivers may use the access line for administration of drugs in the limited prehospital pharmacopoeia but it is equally true that pre-establishment of intravascular access saves a step on arrival to the next level of care Practitioners in todays EDs currently benefit in savings of nursing time from not having to take time to establish IV access in patients transported to the hospital by ALS units This helps both the individual patient with pre-established IV access since ED staff can immediately administer time-critical drugs - including those not in the ALS armamentarium - and also aids the resource-taxed ED whose staff can execute duties other than starting IV lines Furthermore though there is no concrete supporting evidence common wisdom holds that placement of a smaller IV line and fluid administration through that line may facilitate subsequent placement of a larger IV line due to more fluid in the vascular compartment
Thus the balance of evidence from a variety of standpoints outcomes research accepted practice and teaching logistics supports an argument that ability to gain access to the intravascular compartment is an important priority for out-of-hospital care Importantly it should be noted that for ED one could substitute triage tent or other MCI-related care site since intravascular compartment access is of obvious import in MCIdisaster-type situations
Potential role for EASI Mechanism of subcutaneous infusion Subcutaneously administered drugs and infusates must traverse an interstitial matrix to enter the vascular or lymphatic system The interstitiums resistance to drug permeation can be envisioned as functioning like a three-dimensional filter through which drugsinfusates must pass There are large molecules such as elastin and collagen inhabiting a matrix of hydrated gel-like glycosaminoglycans and proteoglycans Among the glycosaminoglycans is hyaluronan which contributes to the resistance of fluid flow through the interstitium Though hyaluronan is found in lower concentration than collagen in the skin it plays a disproportionately large role in resisting fluid movement3 Hyaluronidase modifies connective tissue permeability via hydrolyzing hyaluronic acid effecting a cleavage of the glucosaminidic bond between N-acetylglucosamine and glucuronic acid moieties The cleavage results in a decrease in viscosity of the cellular cement and promotes diffusion of injected fluids facilitating their absorption The decrease in viscosity is reversed within 24 hours due to the rapid inactivation of the hyaluronidase enzyme and also due to the rapid turnover rate of skin hyaluronan4 5 So-called spreading agents historically derived from animal extracts have been used clinically to facilitate dispersion and absorption of other drugs for over 50 years4 The extensive history of spreading agent use was relevant to the FDA review of the new recombinant enzyme Based in part upon the longtime uses of nonrecombinant hyaluronidase the FDA approval for Hylenex states the drug is Indicated as an adjuvant to increase the absorption and dispersion of other injected drugs for hypodermoclysis and as an adjunct in subcutaneous urography for improving resorption of radiopaque agents Subcutaneous infusion instead of or prior to IV infusion
Out-of-hospital clinical scenarios vary widely It is certainly true that not all EMS patients or MCI patients need an IV line However it is easy to think of out-of-hospital situations in which rapidly and easily placed intravascular access could be very helpful and in which standard IV catheters may not be the sole solution To name but a few examples there could be a
Single-patient encounter where the IV line is difficult to place
Multi-car motor vehicle crash MVC site attended by many BLS but few ALS providers
Marathon medical support tent confronted with scores of volume-depleted individuals
Building collapse eg in an earthquake with numerous victims in whom simultaneous and timely fluid replacement can stave off crush-mediated renal failure Standard texts such as the American College of Surgeons Advanced Trauma Life Support note that the need for IV access is often present in cases where there is no ability to place an indwelling vascular catheter The ATLS text points out that fluid resuscitation in clinically challenging environments eg austere conditions MCI situations is often of sufficient criticality that in the absence of IV access hydration should be attempted through oral or rectal routes As the ACS Committee on Trauma writes oral hydration has obvious aspiration and absorption risks and rectal clysis as it is denoted in the ATLS text presents obvious logistic and patient comfort issues in the field1 It is thus clear that there is a potential role for EASI access if such access extends the ability to usefully reach the intravascular compartment In terms of its potential as a mechanism for out-of-hospital fluid replacement and as a route for drug administration EASI warrants attention in the form of a trial
Compared to the current standard of IV and perhaps intraosseous line placement by ALS-level providers EASI access could enable out-of-hospital responders ALS as well as lower echelon providers to achieve intravascular access in more patients more quickly more reliably and with less pain We thus plan to conduct the EASI Access study for out-of-hospital providers as a mechanism to investigate whether EASI access can accrue the hypothesized advantages The study will begin with ALS-level providers The ultimate plan should ALS provider EASI prove efficient will be to assess whether simple placement of EASI access by non-ALS providers can extend the reach of advanced care providers in situations where need for IV access outstrips available resources
Not specifically the goal of the EASI Access trial but potentially relevant for any future use of Hylenex is that the ability to avoid IV access may be occasionally useful in the acute care setting In patients who are very young or cachectic or simply need IV access for fluid replacement EASI may be able to obviate the need for possibly numerous IV sticks and their attendant discomfort The low but nonzero rate of IV access complications eg thrombosis phlebitis in general may also be avoided by use of EASI access The EASI Access investigation very clearly does not offer these potential advantages to the current trials study subjects but the hypothetical advantages to avoiding IV placement do provide further possible relevance to any positive findings in the EASI Access study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None