Clinical evaluation of large volume subcutaneous injection tissue effects, pain, and acceptability in healthy adults.

Determining feasibility and tolerability of large volume viscous subcutaneous injection may enable optimized, intuitive delivery system design. A translational early feasibility clinical study examined large volume subcutaneous injection viability, tolerability, acceptability, tissue effects and depot location for ~1, 8, and 20 cP injections at volumes up to 10 ml in the abdomen and 5 ml in the thigh in 32 healthy adult subjects. A commercial syringe pump system delivered 192 randomized, constant rate (20 µl/s) injections (6/subject) with in-line injection pressure captured versus time. Deposition location was qualified via ultrasound. Tissue effects and pain tolerability were monitored through 2 hours post-injection with corresponding Likert acceptability questionnaires administered through 72 hours. All injection conditions were feasible and well-tolerated with ≥79.3% favorable subject responses for injection site appearance and sensation immediately post-injection, increasing to ≥96.8% at 24 hours. Mean subject pain measured via 100 mm visual analog scale increased at needle insertion (6.9 mm, SD 10.8), peaked during injection (26.9 mm, SD 21.7) and diminished within 10 minutes post-removal (1.9 mm, SD 4.2). Immediate injection site wheal (90.9%) and erythema (92.6%) formation was observed with progressive although incomplete resolution through 2 hours (44.6% and 11.4% remaining, respectively). Wheal resolution occurred more rapidly at lower viscosities. Most subjects (64.5%) had no preference between abdomen and thigh. Correlations between tissue effects, injection pressure and pain were weak (Pearson's rho ± 0-0.4). The large volume injections tested, 1-20 cP viscosities up to 10 ml in the abdomen and 5 ml in the thigh, are feasible with good subject acceptability and rapid resolution of tissue effects and pain.

Clinical Evaluation of an Investigational 5 mL Wearable Injector in Healthy Human Subjects.

An investigational wearable injector (WI), the BD Libertas Wearable Injector (BD Libertas is a trademark of Becton, Dickinson and Company), was evaluated in an early feasibility clinical study for functional performance, tissue effects, subject tolerability, and acceptability of 5 mL, non-Newtonian ~ 8 cP subcutaneous placebo injections in 52 healthy adult subjects of 2 age groups (18-64 years and ≥ 65 years). Randomized WI subcutaneous injections (n = 208, 4/subject) were delivered to the right and left abdomen and thigh of each subject, 50% (1 thigh and 1 abdomen) with a defined movement sequence during injection. Injector functional performance was documented. Deposition was qualified and quantified with ultrasound. Tissue effects and tolerability (pain) were monitored through 24 hours with corresponding acceptability questionnaires administered through 72 hours. WI (n = 205) automatically inserted the needle, delivered 5 mL ± 5% in 5.42 minutes (SD 0.74) and retracted. Depots were entirely (93.2%) or predominantly (5.4%) localized within the target subcutaneous tissue. Slight to moderate wheals (63.9%) and erythema (75.1%) were observed with ≥ 50% resolution within 30-60 minutes. Subject pain (100 mm Visual Analog Scale) peaked mid-injection (mean 9.1 mm, SD 13.4) and rapidly resolved within 30 minutes (mean 0.4 mm, SD 2.6). Subjects' peak pain (≥ 90.2%), injection site appearance (≥ 92.2%) and injector wear, size, and removal (≥ 92.1%) were acceptable (Likert responses) with 100% likely to use the injector if prescribed. Injection site preference was divided between none (46%), abdomen (25%), or thigh (26.9%). The investigational WI successfully delivered 5 mL viscous subcutaneous injections. Tissue effects and pain were transient, well-tolerated and acceptable. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

Worldwide Injection Technique Questionnaire Study: Population Parameters and Injection Practices.

From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries took part in one of the largest surveys ever performed in diabetes. The goal was to assess patient characteristics, as well as historical and practical aspects of their injection technique. Results show that 4- and 8-mm needle lengths are each used by nearly 30% of patients and 5- and 6-mm needles each by approximately 20%. Higher consumption of insulin (as measured by total daily dose) is associated with having lipohypertrophy (LH), injecting into LH, leakage from the injection site, and failing to reconstitute cloudy insulin. Glycated hemoglobin values are, on average, 0.5% higher in patients with LH and are significantly higher with incorrect rotation of sites and with needle reuse. Glycated hemoglobin values are lower in patients who distribute their injections over larger injection areas and whose sites are inspected routinely. The frequencies of unexpected hypoglycemia and glucose variability are significantly higher in those with LH, those injecting into LH, those who incorrectly rotate sites, and those who reuse needles. Needles associated with diabetes treatment are the most commonly used medical sharps in the world. However, correct disposal of sharps after use is critically suboptimal. Many used sharps end up in public trash and constitute a major accidental needlestick risk. Use of these data should stimulate renewed interest in and commitment to optimizing injection practices in patients with diabetes.

Worldwide Injection Technique Questionnaire Study: Injecting Complications and the Role of the Professional.

From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries participated in one of the largest surveys ever performed in diabetes. The first results of this survey are published elsewhere in this issue. Herein we report that the most common complication of injecting insulin is lipohypertrophy (LH), which was self-reported by 29.0% of patients and found by physical examination in 30.8% by health care professionals (HCPs). Patients with LH consumed a mean of 10.1 IU more insulin daily than patients without LH. Glycated hemoglobin levels averaged 0.55% higher in patients with vs without LH. Lipohypertrophy was associated with higher rates of unexplained hypoglycemia and glycemic variability as well as more frequent diabetic ketoacidosis, incorrect rotation of injection sites, use of smaller injection zones, longer duration of insulin use, and reuse of pen needles (each P<.05). Routine inspection of injection sites by the HCP was associated with lower glycated hemoglobin levels, less LH, and more correct injection site rotation. Patients were also more likely to rotate correctly if they received injection instructions from their HCP in the past 6 months. Fewer than 40% of patients claimed to have gotten such instructions in the past 6 months, and 10% said that they have never received training on how to inject correctly despite injecting for a mean of nearly 9 years. Use of these data should stimulate renewed commitment to optimizing insulin injection practices.