Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00386386 |
| Other study ID # |
Hylenex1 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
October 6, 2006 |
| Last updated |
March 12, 2008 |
| Start date |
May 2007 |
| Est. completion date |
December 2007 |
Study information
| Verified date |
March 2008 |
| Source |
Massachusetts General Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
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 (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:
- 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 (e.g. 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 (e.g. 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 field.1 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 (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.
