Recombinant Hyaluronidase in Out-of-Hospital Setting: The EASI Access Trial
|First Received Date ICMJE||October 6, 2006|
|Last Updated Date||March 12, 2008|
|Start Date ICMJE||May 2007|
|Primary Completion Date||December 2007 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00386386 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Pain associated with subcutaneous infusion vs. IV infusion|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Recombinant Hyaluronidase in Out-of-Hospital Setting: The EASI Access Trial|
|Official Title ICMJE||Enzymatically Augmented Subcutaneous Infusion (EASI) In Out-Of-Hospital Care|
The study's 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 (e.g. 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.
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 (e.g. venous collapse in hypotension), positioning (e.g. 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" (i.e. patient) and "environment" (i.e. 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 illnesses.1 In addition, literature addressing MCI situations (e.g. crush injuries) makes a strong case for the importance of fluid replacement.2 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 today's 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 MCI/disaster-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 interstitium's resistance to drug permeation can be envisioned as functioning like a three-dimensional filter through which drugs/infusates 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 movement.3 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 hyaluronan.4, 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 years.4 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:
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 (e.g. 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 trial's 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 Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Other: hypodermoclysis via recombinant hyaluronidase-facilitated subcutaneous infusion
|Study Arm (s)||1
Subject receives two infusions: One by EASI Access and one by IV access, at different sites
Intervention: Other: hypodermoclysis via recombinant hyaluronidase-facilitated subcutaneous infusion
|Publications *||Soremekun OA, Shear ML, Patel S, Kim GJ, Biddinger PD, Parry BA, Yialamas MA, Thomas SH. Rapid vascular glucose uptake via enzyme-assisted subcutaneous infusion: enzyme-assisted subcutaneous infusion access study. Am J Emerg Med. 2009 Nov;27(9):1072-80.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||December 2007|
|Primary Completion Date||December 2007 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older|
|Accepts Healthy Volunteers||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00386386|
|Other Study ID Numbers ICMJE||Hylenex1|
|Has Data Monitoring Committee||No|
|Responsible Party||Stephen THomas, MGH|
|Study Sponsor ICMJE||Massachusetts General Hospital|
|Collaborators ICMJE||Baxter Healthcare Corporation|
|Information Provided By||Massachusetts General Hospital|
|Verification Date||March 2008|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP