A Study Assessing an Injection Port for Administration of Insulin

Transcription

1 Feature Article / Blevins et al. A Study Assessing an Injection Port for Administration of Insulin Thomas Blevins, MD; Sherwyn L. Schwartz, MD; Bruce Bode, MD; Stephen Aronoff, MD; Claire Baker, MD; Kay T. Kimball, PhD; Ronald B. Harrist, PhD; Chris Donnelly; Lauren C. Burns; and Anna M. Wooldridge Abstract Objective. To compare an injection port (I-Port), a disposable device through which multiple doses of insulin may be injected, to standard multiple dose insulin administration. Design. Prospective, randomized crossover study. Methods. Seventy-four patients with diabetes being treated with daily injections of insulin were recruited at five clinical sites. The patients were randomly assigned to two of three treatment regimens: 1) standard injection (SI), 2) a single I-Port device, or 3) two separate I-Port devices (Dual I-Port) with each treatment regimen lasting for 3 weeks. Participants in the single I-Port regimen injected both regular human or rapid-acting insulin and insulin glargine through the same device, whereas participants in the Dual I-Po r t regimen injected each type of insulin through two separate devices. Participants were evaluated by measurements of glycosylated albumin and study questionnaires. Results. Participants glycosylated albumin was not significantly different between SI, single I-Po r t, and Dual I-Po r t treatment regimens (P = 0.99 for SI vs. single I-Po r t and P = 0.97 for single I-Po r t vs. Dual I-Po r t). Fifty of 72 participants (69.4%) reported that the I-Po r t was useful and helpful in the management of their diabetes. Conclusions. This study supports the utility and efficacy of administering multiple doses of insulin through a single I-Po r t device and concludes that the I-Po r t is a viable alternative to SI. Address correspondence to Chris Donnelly, Patton Medical Devices, 3108 North Lamar Blvd, Austin, Texas In 2005, approximately 7% of the U.S. population (~20.8 million people), had diabetes, with an estimated 1.5 million new cases diagnosed annually. 1,2 According to data provided by the American Association of Clinical Endocrinologists, 3 more than two-thirds of people with type 2 diabetes have suboptimal glucose control (i.e, hemoglobin A 1c [A1C] level > 6.5%). This level of control increases the risk of both short- and long-term complications. Studies have shown that intensive insulin therapy improves metabolic control in people with type 1 diabetes. In addition, recent evidence suggests that glycemic control is also vital in those with type 2 diabetes. 4,5 In turn, improved diabetes control is associated with delayed onset and slowed progression of long-term complications. 6 Many patients require multipledose insulin therapy to achieve acceptable glycemic control. Variable adherence to insulin treatment is believed to contribute to poor metabolic control. 7 Evidence suggests that a noninvasive or minimally invasive treatment option will help facilitate adherence for individuals whose reasons for nonadherence range from inconvenience of therapy to needle aversion. 8 In an effort to address the need for a minimally invasive delivery alternative to insulin injections, the I-Po r t injection port was developed. The I-Po r t is a disposable, lowprofile injection port through which prescribed medications, including 197

2 Feature Article / Insulin Insertion Port Figure 1. I-Port Illustration insulin, can be injected subcutaneously from a syringe or pen without repeated needle punctures of the skin. The I-Port is suitable for adults and children in home and health care facility environments and remains on the body while bathing, sleeping, and exercising. It can accommodate up to 75 injections and may be worn for up to 72 hours. Application of the I-Port is accomplished by an insertion needle, which guides a soft cannula (a small, flexible tube) under the skin. Insulin is then injected through the I-Port by the needle of a syringe or pen. The needle remains above the surface of the skin while the medication is immediately delivered through the soft cannula and into the subcutaneous tissue. Illustrations of the I-Port are provided in Figure 1. The primary objective of this study was to investigate the function of the I-Port device while maintaining a level of diabetes control in patients receiving daily injections of insulin through the I-Port comparable to those receiving injections in the standard fashion (SI). The secondary objective was to determine participant attitudes regarding the I-Port device. The primary evaluation marker for diabetes control was glycosylated albumin. Secondary markers were evaluated with standard quality-of-life questionnaires and adverse events related to the I-Port device, including incidence 198 of erythema > 2 cm in diameter, incidence of induration > 1 cm in diameter, and incidence of suppuration at the I-Port application site. RESEARCH DESIGN AND METHODS Study Design This study used a multicenter, randomized, prospective, controlled, open-label, two-period crossover design. Individuals who were routinely treated with intensive, multi-injection insulin therapy using regular human or rapid-acting insulin and insulin glargine were recruited. The participants entered a 2-week screening period, and if the acceptance criteria were satisfied and written informed consent was given, they were randomly assigned by means of a computergenerated blind random process to one of four cohorts. The first 3-week treatment phase consisted of insulin administration either by SI, a single I-Port device, or two separate I-Port devices (Dual I-Port). Using a two-period crossover design, the participants were reassigned to an alternate treatment regimen for an additional 3 weeks as indicated in Figure 2. All regimens administered regular human or rapid-acting insulin and insulin glargine, a minimum of two injections daily of either Novolin, Humulin, NovoLog, Humalog, or Apidra and no more than one injection of Lantus daily. Participants took their insulin preparations at the usual time and dosage as prescribed by their physician. The only modification of their regimen was adherence to the randomized direction of administering insulin either by means of SI (i.e., needle and syringe or insulin pen by direct skin puncture) or by means of injecting both their regular human or rapidacting insulin and insulin glargine via a single I-Port (separating the dose of insulin glargine from the regular human or rapid-acting insulin by at least 60 minutes) or by means of Dual I-Port. Participants were required to continue to use the SI delivery method they were practicing before entry into the study. For the Dual I-Port treatment regimen, one I-Port device was dedicated to receive regular human and rapid-acting insulin and another I-Port device was dedicated to receive insulin glargine. Reinsertion of a new I-Port device was required to be applied at least 3 inches from the previous insertion site every 72 hours. This clinical study included five assessment visits. Participants were trained on proper application, use, and removal of the I-Port at the start of the trial and were provided with a LifeScan OneTouch UltraSmart home blood glucose meter as incen-

3 Feature Article / Blevins et al. Screening (2 weeks) Trial Start 74 Participants Cohort 1 18 Participants Cohort 2 20 Participants Cohort 3 18 Participants Cohort 4 18 Participants Standard Injections Dual I-PORT 1 ET 2 ET Standard Injections Dual I-PORT 3 ET 2 ET 1 ET 1 ET Final Observation (1 week) Trial End 64 Participants Figure 2. Study Design. ET, early termination from study; Single I-Po r t, the treatment phase where the participants used one I-Po r t through which both regular human or rapid-acting insulin and insulin glargine was injected; Dual I-Port, the treatment phase where the participants used two I-Port devices: one through which regular or rapidacting insulin was injected and one through which insulin glargine was injected; Standard Injections, the treatment phase where the participants used a needle syringe or pen to inject regular human or rapid-acting insulin and insulin glargine as prescribed before study entry. tive to participate in the study and to record their blood glucose levels. Participants meters were downloaded at each clinical site during the treatment phase visits using the LifeScan OneTouch UltraSmart software, and blood samples were collected and sent to a central laboratory where A1C, glycosylated albumin, and blood glucose were measured. Glycosylated albumin, which correlates well with A1C determinations, 9 was measured as an indicator of short-term glycemic control. Before random assignment to a cohort, all participants completed the General Diabetes Management questionnaire, which contained, among others, questions regarding their perception of their diabetes control and overall health rated on a 5-point Likert scale. At the end of the single I-Po r t treatment, participants were again questioned about their diabetes control and overall health. Abnormal clinical or laboratory findings were considered adverse events. The investigators monitored and recorded adverse events throughout the study and classified each event in accordance with the World Health Organization guidelines of the Collaborating Centre for International Drug Monitoring Health Product Safety Information Division. Interim visits or telephone consultations occurred as necessary to assist with participant questions related to the use of the I-Po r t device or SI. Adverse events included the occurrence of erythema or suppuration or induration at the injection site while wearing an I-Po r t device and were considered relevant to assessing device functionality. Statistical Methods Analysis of variance for a 2 2 crossover study was used to examine the intersubject effects of sequence (cohort) and the intrasubject effects of time of treatment (first or second period) and treatment. Because of the nature of the intervention, no effects were expected related to sequence and time of administration. These 199

4 Feature Article / Insulin Insertion Port assumptions were checked before combining participants with the same experimental exposures for the equivalence analyses. The analyses assumed that there were no carryover effects. Equivalence analysis was used to test the hypothesis that use of the I-Po r t device as a means of insulin administration is of equal value to the use of SI for controlling glycosylated albumin, as well as to test the hypothesis that use of a single I-Po r t to inject both insulin preparations is of equal value to the use of two separate I-Po r t devices. 10 The comparison between the single I-Po r t and the Dual I-Po r t was necessary to ensure that the analysis between the single I-Po r t and SI was not influenced by injecting both insulin preparations through the same device. The Dual I-Po r t group was used solely for this reason. Equivalence analysis to compare SI to two separate I-Po r t devices was not an objective of this study; therefore, this analysis was not performed. The distributions of the paired responses from the General Diabetes Management questions administered at baseline and after the I-Po r t treatment analyses were compared by symmetry analyses (a generalization of McNemar s test that determines whether row and column marginal frequencies are equal). A priori power calculations for the equivalence analysis showed that a mean of 114% in the I-Po r t treatment group would be declared equivalent to the SI group with 80% power at 5% significance level when the range of equivalence is 20 to 20%. Paired t-tests were used to compare participants perceptions of their diabetes control and overall health. Stata statistical software was used for the statistical analysis. 11 All tests were conducted at the 5% level, and no correction for multiple testing was made in the significance levels. RESULTS Study Population Participants were enrolled at five clinical sites from October 2006 through January The initial study population consisted of 74 participants (40 male) aged years (median 48 years) who at baseline had type 1 (56 participants) or type 2 (18 participants) diabetes for a minimum of 6 months. Of the 74 people who qualified to participate in the study, 64 (86%) completed all five visits. Six of the 10 participants (8.1%) who did not complete the trial terminated for device-related reasons including adhesive failure, wear discomfort, high blood glucose levels (> 200 mg/dl), cannula bends, and adverse events (Table 1). Four participants (5.4%) terminated for non-device related reasons. Single I-Po r t Versus SI and Single I-Po r t Versus Dual I-Po r t Analyses of variance for 2 2 crossover studies showed no sequence or time effects that would affect the test of equivalence of treatments in glycosylated albumin during the 6-week treatment phase. For glycosylated albumin, the test limits for equivalence of SI versus the single I-Po r t were 98.9 and 107.3%, which are within the equivalence limits of % (P = 0.99). The test limits for equivalence of the single I-Po r t versus the Dual I-Po r t were 99.5 and 110.9%, which are within the equivalence analysis limits (P = 0.97). The A1C values were similar among Table 1. Average Glycosylated Albumin SI Glycosylated Albumin Single I-Po r t 200 all cohorts at the initiation and completion of the study. Blood glucose readings captured from home blood glucose monitors and fasting blood glucose levels were not analyzed because of variability in sequence and timing of testing. The primary evaluation data are presented in Table 2. Participants Attitudes Toward the I-Po r t Through two questionnaires, participants perceptions of their diabetes control and overall health during the I-Po r t treatment regimen were compared to answers completed during randomization into the study. In 72 paired responses, a significantly larger number of subjects (62.5% SI vs. 48.1% I-Po r t) reported that it was hard to stay in control of diabetes during the SI than during the I-Po r t treatment (P = 0.016). In 71 paired responses, a larger number of subjects (68.7% I-Po r t vs. 61.1% SI) rated their overall health very good or excellent when using the I-Po r t than when using SI (P < 0.001). Fifty of 72 participants (69.4%) indicated that they felt the I-Po r t was useful and helped them manage their diabetes. Fifty-one of 72 participants (70.8%) indicated that the I-Po r t was not at all difficult to use whereas 12 participants (16.7%) indicated that it was slightly difficult. When assessing the wear comfort of the I-Po r t, 49 of 72 participants (68.1%) stated that they forgot they were wearing the device at times during the study. Adverse Events Of the 74 participants wearing a single I-Po r t device, three (4.1%) reported erythema, one (1.4%) reported suppuration, and none reported induration during 74 Dual I-Po r t Cohort 1 n = ± ± N/A Cohort 2 n = ± N/A Cohort 3 n = 17 N/A ± ± Cohort 4 n = 16 N/A ± ± Values are presented as means and standard deviations and include all available data.

5 Feature Article / Blevins et al. Table 2. Incidence of Adverse Events Single I-Port Relationship to Single I-Port Dual I-Port Standard Injections Erythema 3 Certain 2 Induration Suppuration 1 Certain 1 Other Adverse Events Bruising at insertion 1 Certain site Stomach flu 1 Elevated blood 1 Certain 1 glucose* Ear infection 1 Severe hyperglycemia 3 Certain Folliculitis of the right 1 Unlikely 1 groin Gastroenteritis 1 Sinus congestion 1 Upper respiratory 1 infection Skin irritation 1 Certain Itching at insertion site 1 Certain Frequent hypoglycemia 1 Common cold 2 *Participant was randomized into Cohort 4 and withdrew after 1 week of being in cycle 1. Study coordinator reported in the Subject Master File, Participant reports having problems with his insulin pen, which may have led to the participant not receiving the correct amount of insulin and withdrawing from the study. The participant expressed in the I-Po r t questionnaire that he had a very positive opinion of the I-Port device. Participant was randomized into Cohort 1 and withdrew after 1 week of being in cycle 2. Indications suggest severe hyperglycemia was caused by I-Port malfunction: cannula bends. 3-week periods. This is equivalent to.054 events per period or.935 events per year. None of these three events were reported during the Dual I-Po r t treatment regimen. All of these events, although unlikely, can occur when wearing indwelling catheters or pump infusion sets. Five other adverse events potentially related to use of a single I-Po r t device were reported in four participants (5.4%), a rate of events per participant per period or 1.17 events per participant per year. The five events were severe hyperglycemia (reported three times in the same participant, resulting in withdrawal from the trial); skin irritation from the adhesive and itching at the insertion site (both in same participant); bruising at the insertion site; and elevated blood glucose (resulting in withdrawal from the trial). There was one nonrelated adverse event reported during the single I-Po r t treatment regimen: folliculitis, resulting in a rate of events per period or 0.23 per participant per year. Of the 36 participants wearing Dual I-Po r t devices over 36 3-week periods, one (2.8%) reported elevated blood glucose judged to be possibly related to the study device, a rate of events per period or 0.48 per participant per year. There were three nonrelated adverse events reported during the Dual I-Po r t treatment regimen: one sinus congestion, one ear infection, and one common cold (reported twice by the same participant), a rate of events per period or 1.44 per participant per year. Complete adverse event data are presented in Table 2. CONCLUSIONS Using measures that could detect significant changes in glycemic control, this study supports the conclusion that a single I-Po r t device functions effectively when giving regular human or rapid-acting insulin and insulin glargine. No regular pattern of termination in the six of 74 participants (8.1%) who withdrew for device-related events was seen, and no permanent harm occurred from use of the I-Po r t device during the course of the study. Diabetes control as measured by glycosylated albumin was similar in participants taking multiple daily doses of insulin using a single I-Po r t device and SI. References 1 Steinbrook R: Facing the diabetes epidemic: mandatory reporting of glycosylated hemoglobin values in New York City. N Engl J Med 354: , American Diabetes Association: National Diabetes Fact Sheet 2005 [article online]. Available online from NationalDiabetesFactSheetRev.pdf. Accessed 23 January

6 Feature Article / Insulin Insertion Port 3 Beckley ET: Nation s blood glucose out of control. DOC News 2:12, The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 328: , Skyler JS: Effects of glycemic control on diabetes complications and on prevention of diabetes. Clin Diabetes 22: , Nathan DM: Long-term complication of diabetes mellitus. N Engl J Med 328: , Morris AD, Boyle DI, McMahon AD, Greene SA, MacDonald TM, Newton RW: Adherence to insulin treatment, glycemic control, and ketoacidosis in insulin dependent diabetes mellitus. Lancet 350: , Wagner J, Malchoff C, Abbot G: Invasiveness as a barrier to self-monitoring of blood glucose in diabetes. Diabetes Tech Therapeut 7: , Ryan EA, Stark R, Crockford PM, Suthijumroon A: Assessment of value of glycosylated albumin and protein in detection of gestational diabetes. Diabetes Care 10: , Rani S, Pargal A: Bioequivalence: an overview of statistical concepts. Indian J Pharmacol 36: , StataCorp: Stata statistical software, release 9.2. StataCorp., College Station, Texas, 2006 Thomas Blevins, MD, is the chief executive officer and director at Texas Diabetes & Endocrinology, in Austin. Sherwyn L. Schwartz, MD, is chief executive officer and chief medical officer at the Diabetes and Glandular Disease Clinic Research Association in San Antonio, Texas. Bruce Bode, MD, is a diabetes specialist at Atlanta Diabetes Associates in Georgia. Stephen Aronoff, MD, is the director at the Research Institute of Dallas in Texas. Claire Baker, MD, is a diabetes specialist at Diabetes and Endocrine Associates in Omaha, Nebr. Kay T. Kimball, PhD, is co-founder and owner of Statistical Design and Analysis in Austin, Texas. Ronald B. Harrist, PhD, is an associate professor of biostatistics at the University of Texas School of Public Health in Austin. Chris Donnelly is the executive vice president and chief financial officer, and Lauren C. Burns and Anna M. Wooldridge are clinical affairs associates at Patton Medical Devices, LP, in Austin, Texas. Note of disclosure: Drs. Blevins, Bode, and Aronoff have received research support from Patton Medical Devices, which manufactures the I-Po r t device. The research company headed by Dr. Schwartz has received research support from numerous pharmaceutical and medical device companies, including Patton Medical Devices (complete list on file). Drs. Kimball and Harrist are paid biostatistical consultants for Patton Medical Devices. Mr. Donnelly, Ms. Burns, and Ms. Woolridge are employed by and stock shareholders in Patton Medical Devices. Mr. Donnelly is also a member of the company s board of managers. 202