A single blind, randomised, 8 way crossover study to compare the blood volume and pain perception of capillary blood sampling

Transcription

1 A single blind, randomised, 8 way crossover study to compare the blood volume and pain perception of capillary blood sampling There currently exist a plethora of single use blood sampling devices for obtaining capillary blood samples, most commonly for use in testing of blood sugar levels in diabetes. However there are limited numbers of studies comparing the adequacy of these devices in terms of the blood volume they can generate, and also in terms of the pain produced during the sampling process. We designed a study to look at eight devices using these two parameters, with one device serving as a reference (Unistik 3 PC, Owen Mumford Ltd). Introduction There are few recent studies which compare capillary blood sampling devices in terms of the adequacy of blood volume generated, and also with regards to the pain produced during the sampling procedure. In general, most samples taken for the purposes of monitoring capillary blood glucose are taken from the distal part of the fingers, which tend to be more sensitive, but also to more accurately reflect the true level of blood glucose when compared to samples taken from the arms or abdominal skin. Therefore a device which can show a consistent reduction in pain compared to its competitors, whilst still producing adequate blood volume for use by today s blood glucose monitoring devices should be welcomed by patients, especially those who are monitoring blood glucose on a more frequent basis.

2 Methods Inclusion and exclusion criteria The study was designed as an eight way crossover, single blind, randomised study to look at blood volume generated (both unassisted and assisted) and pain perception, comparing eight different devices (with the Unistik 3 PC device as the reference device) in healthy adult volunteers. Volunteers were selected from a panel who had offered their services to Simbec Research Ltd for the purposes of investigating new medicines and devices. All volunteers had to be healthy, between the ages of 18 and 70, with no abnormalities of perception in the fingers (as assessed by a physician), no evidence of skin disease affecting the digits, no cornification on the distal aspects of the fingers, no history of diabetes (or evidence of same on screening lab tests), no abnormalities of platelet count and negative pregnancy tests for the female volunteers. All volunteers freely gave written informed consent to participate in the study. Volunteers were excluded if they had taken any prescription or OTC medication within 2 weeks of starting the study which might affect either pain perception or blood volume obtained, had any clinically significant medical conditions or abnormalities in laboratory tests seen at screening (including positive tests for HIV or Hepatitis B or C), had a positive urine screen for drugs of abuse taken at screening and in addition for female volunteers they were excluded if they had a positive pregnancy test during the study (testing was carried out each time they attended). Study conduct The study was approved by the local research ethics committee prior to any recruitment being undertaken. A total of 26 volunteers (age range 18-64: 8 males, mean age 30.3 years, mean weight 93.7kg, mean height 1.81m: 18 females, mean age 39.7 years, mean weight 71kg, mean height 1.60m) were enrolled into the study, based on statistical calculations to enable the detection of statistically significant differences in both blood volume and pain perception. These volunteers were then randomly assigned to treatment groups according a randomisation code generated by Simbec Research using the PROC PLAN procedure of SAS (version ). Eight devices were tested, from 7 different manufacturers (table 1). Environmental conditions were kept as consistent as possible, with room temperature between 18 and 25 C (recorded in daily temperature log). Devices were randomly assigned to be tested on one of 8 sites on each volunteer (the medial and lateral aspects of the middle and ring fingers of each hand), with each device being tested at the same site on that volunteer on each occasion. There was a minimum 48 hour gap between testing sessions, to allow recovery of the testing sites. Only two testers (JM and RT) were used, with one (JM) conducting the majority of the tests.

3 TABLE 1: Device Characteristics Brand Unistik 3PC (reference device) Manufacturer/ Owen distributor Mumford Needle/Blade Needle Gauge 23G Top/Side firing Side Needle 1.8 penetration depth (mm) Device firing Semi (semiautomatic or automatic manual) Unistik 3 (Test 1) Accu-Chek Safe- T-Pro Plus (Test 2) BD Genie (Test 3) Surgilance One Step (Test 4) Haemolan ce (Test 5) EZ-Lance (Test 6) Auto Safety Lancet (Test 7) Vitalcare/ Sinda Owen Mumford Roche Diagnostics Becton Dickinson Surgilance HaeMedic Palco Labs Needle Needle Needle Needle Needle Needle Needle 23G 23G 23G 21G 21G 21G 21G Side Top Top Top Top Side Side 1.8 Variable (1.3, or used in this study) Semi-automatic Manual Semiautomatic Semiautomatic Semiautomatic Semiautomatic Semiautomatic

4 Finger pricking was undertaken in standardised fashion. The volunteer washed and dried their hands prior to the first device being tested. They were then seated behind a screen (such that they could not see the device being tested), through which they placed their hand. They were given a sheet with the scoring system for pain (0 4, 0 being no pain and 4 being very severe; the scale included half points), which they then verbally communicated to the person recording pain scores. Devices were tested in the order prescribed by the randomisation; sites were always tested in order 1-8. The actual testing itself was carried out as follows: both site and device to be tested were identified by the tester and a checker. The site was then vigorously rubbed with cotton wool for 5 seconds and the prescribed device was then held against the site for 3 seconds before triggering the device (this was to limit any pressure effect caused by devices which were pressure activated). Pain score was obtained by direct questioning at this time, whilst the unassisted blood volume was being measured. Assisted blood volume was then recorded, using the method detailed below. Following this any adverse events such as after bleeding, device malfunction or double puncture were noted. This sequence was repeated until all 8 devices had been tested. Between 1 and 2 hours after the initial test, a review was carried out to assess residual pain and any other effects such as bruising at the test site (this was then recorded as an adverse event). Measurement of study parameters Blood volume was measured both unassisted and assisted: unassisted blood volume was taken to be the volume produced from the initial lancing, collected into a 1µl capillary tube for a maximum of 15 seconds (more than one tube to be used if required); assisted blood volume was that volume collected into a 200µl capillary tube after the finger being tested had been massaged 3 times from the hand towards the puncture site, following the collection of the unassisted sample. Pain was measured on a scale of 0 4, including half points. A reference copy of this scale was made available to the volunteers whilst they were undergoing testing. Pain was assessed on 2 occasions; directly following testing, and between 1 and 2 hours after testing. Pain was not recorded as an adverse event during this study, since it was being recorded separately using the above score. The volunteers were directly asked for the score (0-4) that they felt the device warranted. Statistical analysis A statistical analysis plan was written by Simbec Research Ltd and agreed with the study sponsor prior to database lock. Primary efficacy data was the blood volume generated by each device compared to the reference device. Primary safety data was the pain caused by each device when compared to the reference device. Secondary safety data were those adverse events generated and also laboratory safety data from haematology, biochemistry and urinalysis screens. Power calculations for this study were based upon previous data provided by the sponsor, based on their own trials; however we used a slightly different method to obtain the assisted blood volume and therefore this affected the power of the study to detect small differences between devices with regards to this parameter such that differences smaller than 3µl could not

5 be considered to have any statistical significance. At the sponsor s request, additional analyses were carried out comparing all devices to Test 1 (Unistik 3), and these tables have also been included in the results section. Effect A mean unassisted and assisted blood volume (unassisted mean and assisted mean ) was calculated for each subject and each device (across all visits). Descriptive statistics of unassisted mean and assisted mean using n, mean, standard deviation, minimum, median and maximum, by device were presented. Additionally unassisted mean and assisted mean were subjected to an analysis of variance (ANOVA) using fixed effects for site and device and a random effect for subject. Point estimates and 95% confidence intervals were constructed for each of the 7 pair wise comparisons (each test versus reference) along with the presentation of a p-value. No adjustments for multiple comparisons were made. Safety A maximum pain score (pain max ) was calculated for each subject and each device (across all visits). Descriptive statistics of pain max using n, mean, standard deviation, minimum, median and maximum, by device was presented. Additionally pain max was subjected to an analysis of variance (ANOVA) using fixed effects for site and device and a random effect for subject. Point estimates and 95% confidence intervals were constructed for each of the 7 pair wise comparisons (each test versus reference) along with the presentation of a p-value. No adjustments for multiple comparisons were made.

6 Results Blood Volume Statistical Analysis of Mean Blood Volume (µl) Method Admin. LSMeans LSMean Test - Reference 95% C.I. for P-Value Reference 0.41 N/A N/A N/A Test Test Unassisted Test Test Test Test Test Reference N/A N/A N/A Test Test Assisted Test Test Test Test Test Reference (R) : Unistik 3PC Normal; Test 1 : Unistik 3 Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie; Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare). Statistical Analysis of Mean Blood Volume (µl) - All Tests & Reference vs. Test 1 Method Admin. LSMeans LSMean Test/Ref. Test 1 95% C.I. for P-Value Unassisted Test N/A N/A N/A Test Test

7 Test Test Test Test Reference Assisted Test N/A N/A N/A Test Test Test Test Test Test Reference Reference (R) : Unistik 3PC Normal; Test 1 : Unistik 3 Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie; Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare). Side-Firing v. Top Firing Devices Method Side-Firing Top-Firing LSMean Side-Firing Top-Firing LSMeans 95% C.I. for P-Value Unassisted Assisted < (Side-firing: Reference, Test 1, Test 6, Test 7; Top-firing: Test 2, Test 3, Test 4; Test 5)

8 Unassisted blood volume Blood sampling with the Haemolance (Test 5) device resulted in a mean blood volume which was statistically significantly higher than the reference device (p=0.0203). The Auto Safety Lancet (Test 7) device gave a mean blood volume which was statistically significantly lower than the reference device (p=0.0079). Assisted blood volume Blood sampling with the BD Genie (Test 3), Surgilance One Step (Test 4) and Haemolance (Test 5) devices all resulted in mean blood volumes which were statistically significantly higher than the Unistik 3PC Normal device (Reference) (p = , p = 0004 and p = , respectively). Blood sampling with the Auto Safety Lancet (Vitalcare) device (Test 7) resulted in a mean blood volume which was statistically significantly lower than the Unistik 3PC Normal device (Reference) (p = ). Pain Statistical Analysis of Maximum Pain Score

9 Admin. LSMeans LSMean Test - Reference 95% C.I. for P-Value Reference 2.06 N/A N/A N/A Test Test Test Test Test < Test Test Reference (R) : Unistik 3PC Normal; Test 1 : Unistik 3 Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie; Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare). Statistical Analysis of Maximum Pain Score - All Tests & Reference vs. Test 1 Admin. LSMeans LSMean Test/Ref. Test 1 95% C.I. for P-Value

10 Test N/A N/A N/A Test Test Test Test < Test Test Reference Reference (R) : Unistik 3PC Normal; Test 1 : Unistik 3 Normal; Test 2 : Safe-T-Pro Plus; Test 3 : BD Genie; Test 4 : Surgilance One Step; Test 5 : Haemolance; Test 6 : EZ-Lance; Test 7 : Auto Safety Lancet (Vitalcare). Side-Firing v. Top Firing Devices Side-Firing Top-Firing LSMean Side-Firing Top-Firing LSMeans 95% C.I. for P-Value (Side-firing: Reference, Test 1, Test 6, Test 7; Top-firing: Test 2, Test 3, Test 4; Test 5) The Unistik 3 Normal (Test 1) and Auto Safety Lancet (Vitalcare) (Test 7) devices were significantly less painful than the Unistik 3PC Normal device (Reference) (p = and p = , respectively). The Haemolance (Test 5) device was significantly more painful than the Unistik 3PC Normal device (Reference) (p < ). In the additional analysis carried out to look at all devices versus Test 1, all devices apart from Test 7 were statistically significantly more painful than Test 1. Of note, side-firing devices in general were statistically less painful than top-firing devices. Adverse Events There were a total of one hundred and fifty eight (158) adverse events reported during the study, of which one hundred and fifty two (152) were treatment emergent (onset post start of device testing). Ten (10) adverse events were reported following testing with the Unistik 3PC Normal device (Reference). Nineteen (19) adverse events were reported following testing with the Unistik 3 Normal device (Test 1). Nineteen (19) adverse events were reported following testing with the Safe-T-Pro Plus device (Test 2). Twenty nine (29) adverse events were reported following testing with the BD Genie device (Test 3). Twenty eight (28) adverse events were reported following testing with the Surgilance One Step Device (Test 4). Nineteen (19) adverse events were reported following testing with the Haemolance device (Test 5). Nineteen (19) adverse events were reported following testing with the EZ-Lance

11 devices (Test 6). Nine (9) adverse events were reported following testing with the Auto safety Lancet (Vitalcare) device (Test 7). All treatment emergent events were mild in severity and considered to be almost definitely related to the device testing. No action was required and all events completely resolved. The most frequently reported adverse event was Contusion, Reported Term: Bruising Site X 1 (117 events). Other adverse events reported following device testing were Post Procedural Haemorrhage, Reported Term: After Bleeding Site X 1 (34 events) and Device Malfunction (1 event). 1 Where X = Device Testing Site Number i.e. 1 to 8.

12 Discussion This study was designed to compare 8 different capillary blood sampling devices with respect to both blood volume produced (unassisted and assisted) and pain generated by the devices. One device (Unistik 3PC) was used as the reference device (this device is no longer available, having been superseded by the Unistik 3 with CZT ). Seven of the devices were semi-automatic (i.e. the device is fired by pressing a trigger linked to a needle mounted on a spring, which then fires the needle at a pre-set speed, retracting it afterwards so it then cannot be used again); one device (Haemolance (Test 5)) was manually triggered (i.e. the needle is linked directly to a trigger, and the speed of firing and retraction is totally operator dependent- in this case the device could technically be used again [although this would be contrary to the manufacturer s instructions, and sharps policies in any healthcare facilities], since there is no lock-out mechanism to prevent re-use. This device has now been superseded by the Haemolance Plus, which has a semi-automatic action and is nonreusable). The data obtained for blood volume tend to suggest that top firing devices produce a greater blood volume than side firing devices. However since most blood glucose meters available currently will provide results with sample sizes of 0.5-5µl (NHS Purchasing and Supply Agency Centre for Evidence-Based Purchasing: A guide to blood glucose meters on the UK market [available as web page or leaflet]) all of the lancing devices on test would provide an adequate sample for these meters. Top-firing devices in general produced a statistically significantly higher level of pain than side-firing devices, although Test 5 (Haemolance) (top-firing) is a manually fired device and therefore is more dependent on the operator than any of the others; the relative slowness of the lancet motion on firing compared to the semi-automatic devices can allow lateral motion of the needle whilst in the tissues, thereby potentially increasing pain. Analysis of the maximum pain scores showed that in relation to the reference device, both Test 1 (Unstik 3 normal) and Test 7 (Auto Safety Lancet) were statistically significantly less painful, and that Test 5 (Haemolance) was statistically significantly more painful. Test 1 (Unistik 3 Normal) uses the Owen Mumford Comfort Zone Technology (based on the pain gate theory of Melzack and Wall), which uses a series of raised dots around the lancing site to provide an initial nonnoiciceptive sensation, which then acts to mask the pain of lancing and hence decrease perceived pain; given that Test 1 and the reference device are otherwise identical, this suggests that there is some benefit in terms of reduction of pain when using this Comfort Zone Technology. Conclusion All the devices provide an adequate blood volume for use with today s blood glucose monitors; side firing devices seem to provide less volume than top firing devices, but also produce less pain on lancing. The addition of Comfort Zone Technology to the Owen Mumford device produced the lowest overall pain score, and a statistically significant reduction in pain compared to the Unistik 3PC without CZT; this suggests

13 that devices using this or similar technology should perhaps be considered as a firstline for blood glucose sampling, particularly in those who are more apprehensive about undergoing such procedures due to the perceived pain involved. References: Fruhstorfer H, European Journal of Pain (2000) 4: Capillary blood sampling: the pain of single-use lancing devices P Nayyar, AD Batki, H Thomason, GH Thorpe: NHS Purchasing and Supply Agency: Report Lancing Systems (March 2006) (available at (NHS Purchasing and Supply Agency: Blood Glucose Meter and lancing devices evaluations, listing details of various devices evaluated by the Medical Devices Agency and PASA) R Melzack, P.D. Wall: Pain mechanisms: A new theory Science, 150: 171-9, 1965