Reliability of Insulin by Jet Injection
Condition: Diabetes Mellitus
Study type: Interventional
Phase: Phase 4

Summary: 
      Using a specific jet injector for the administration of a rapid-acting insulin analogue has
      been shown to advance the absorption of insulin from the subcutaneous area into the
      bloodstream by 40-50%, when compared to conventional injection by insulin pens. The
      reproducibility of the jet stream method has not been previously determined in vivo. It is
      also unknown how the efficacy of injecting regular insulin by jet stream compares to that of
      rapid-acting analogues injected by conventional pen.

      Objectives: 1. To compare the pharmacologic reproducibility of the rapid-acting insulin
      analogue aspart (Novorapid®) injected by jet-injection to that of the same insulin injected
      with a conventional pen. 2. To compare pharmacokinetic and -dynamic profile of regular
      insulin injected by jet injection to that of aspart insulin injected by conventional pen.

      Study design: Double-blind double-dummy randomized controlled parallel/cross-over
    

Detailed description: 
      1. Introduction Insulin administration by a jet injector is a needle-free alternative to
           conventional administration of insulin by insulin pens or syringes. Jet injectors
           deliver insulin at a high velocity (typically >100m/s) across the skin in the
           subcutaneous tissue and dispense the insulin over a larger area than insulin injected
           with a syringe. This significantly accelerates absorption of rapid-acting insulin from
           the subcutaneous area into the systemic circulation.

           Reproducibility of the insulin effect is an essential, but easily overlooked, issue for
           a product that needs to be administered so frequently in daily practice. When identical
           doses of aspart insulin were injected by a common syringe on two different days
           separated by at least a week, the intra-individual and inter-individual variability of
           various pharmacokinetic and -dynamic parameters was found to vary between 11-21% and
           18-36%, respectively. Reproducibility has not been investigated when insulin was
           administered by jet injectors. The investigators previous studies indicated smaller
           between-subjects variability in insulin absorption after injection by this jet injector
           than after injection by conventional pen, providing some evidence that reproducibility
           is at least comparable, but potentially even better when using a jet injector.

           The aim of the present research proposal is to compare the variability of the metabolic
           effect of insulin aspart when administered by jet injection to that when injected by
           conventional insulin pen, under controlled experimental conditions.

           An additional aim is to investigate the pharmacokinetic and -dynamic comparability
           between regular soluble insulin injected by the jet stream device with aspart insulin
           administered by conventional pen. The reason the investigators wanted to investigate the
           comparability is that rapid-acting insulin analogs are not worldwide available and very
           costly compared to regular insulin. If you could achieve the same pharmacological
           benefits as rapid acting insulin with a less costly type of insulin, this would be of
           great benefit for patients with diabetes in less developed countries.

        2. Hypotheses The variability of the metabolic effect of insulin administered
           subcutaneously by jet injection is similar to or better than that of insulin
           administered by a conventional insulin pen. The investigators also hypothesize that the
           metabolic effect of soluble insulin administered by jet injection is similar to that of
           insulin aspart administered by conventional insulin pen.

        3. Study Population For this study, a total of 30 healthy volunteers will be recruited.
           Subjects are potentially eligible when they are between 18 and 50 years of age and in
           good clinical condition. Additional participants will be recruited in case of drop-out.

        4. Investigational medicinal products Main study: Insulin aspart (Novorapid® Penfill 100
           units/ml, 3 ml ampoule): rapid-acting analogue of human insulin.

           Sub-study: Regular Human Insulin (Humulin® Penfill 100 units/ml, 3ml ampoule): human
           regular insulin.

        5. Summary of known and potential risks and benefits Novorapid® insulin is indicated for
           the treatment of diabetes mellitus in adults, adolescents and children above the age of
           2 years. The study comprises a risk of hypoglycemia. However, the risk of hypoglycaemia
           during the experiment is negligible, since glucose is measured at 5-10 minute intervals
           and additional glucose will be administered should glucose levels tend to drop below 4.8
           mmol/l. Intravenous glucose 20% may cause local irritation and occasionally phlebitis.

        6. Methods 6.1 Randomisation The study will have a randomised controlled parallel design.
           Randomisation will be done by a computer program with the use of blocks of two subjects,
           to randomize which of the two devices will contain insulin and which placebo solution.
           This will ensure that equal number of subjects will have the experiment with the
           investigational product (InsujetTM pen) or with the control device (Novopen® IV insulin
           pen).

           To ensure blinding, both pen devices will be prepared by a nurse who is not otherwise
           involved in conducting the experiments. There is no indication for prematurely breaking
           the randomisation code, as subjects will receive the same amount of insulin with one of
           the two devices in each experiment, with frequent glucose-monitoring to prevent
           hypoglycemia.

           6.2 Study procedures Potentially eligible study participants will be recruited using
           websites or by using the RUMC social media. Should this be insufficient, advertisements
           in local newspapers will be placed. Eligibility will be determined at the screening
           visit after a medical interview and physical examination.

           Experimental procedures All participants will be examined on two occasions, within 1
           week, with one of the two devices containing insulin and the other device as a placebo
           device.

           Patients will be instructed to consume a low-glycemic index meal the evening before
           experiments and remain in fasting condition from 20:00 hours onwards.

           On the first and second experimental day, participants will be admitted to the research
           unit at 08.00 hours in fasting condition and having abstained from smoking, alcohol use
           and caffeine use for at least 24 hours. A catheter will be inserted in retrograde
           fashion in a dorsal hand vein for frequent blood sampling, whereby the hand will be
           placed inside a heated box (air temperature, ~55°C) to arterialize venous blood. Another
           catheter will be inserted in the antecubital vein of the other arm, which will be kept
           patent by saline drip, and which will be used for administration of 20% glucose.

           After cannulations, blood will be taken for direct measurement of plasma glucose and
           stored for later measurement of plasma insulin levels. Thereafter, an independent
           research nurse will administer insulin at a dose of 0.2 units per kg body weight
           subcutaneously at the abdominal site, with either the jet injector (InsujetTM) or the
           conventional pen (Novopen® IV). The device not used for insulin administration will be
           prepared by the research nurse as well. However, this device is empty although to the
           patient it will look and feel the same way as the pens filled with insulin. The insulin
           injection and the simulated injection will be given simultaneously. After injection, the
           administration site will be covered by the research nurse with a bandage to prevent that
           the investigator and patient will be able to see whether there has remained some insulin
           on the skin or not. The investigators as well as the participants will be blinded to
           which pen contains the insulin and which pen was the placebo device. Subsequently, a
           6-hour normoglycemic glucose clamp will be employed, as described previously. To this
           end, glucose 20% will be administered intravenously at a sufficient rate to maintain
           normoglycemia, based on plasma glucose levels measured at 5-minute intervals during the
           first 3 hours and at 10-minute intervals during the remainder of the experiment. Also,
           blood will be drawn and stored at -80°C every 5 minutes during the first hour after
           insulin injection and every 15 minutes during the hour thereafter for later
           determination of plasma insulin and C-peptide levels. During the last four hours,
           insulin will be measured with 30 minutes intervals. Six hours after the insulin
           injection, the experiment will be terminated and the patients will be given a meal. The
           total duration of the study day, including preparation and recovery time, will be 7
           hours.

           Participants will be asked separately to return to the research unit a third time for a
           similar 6-hour normoglycemic glucose clamp. On this occasion, the insulin aspart will be
           replaced by regular soluble insulin. The insulin will be administered by the jet
           injector. Pharmacokinetic and -dynamic data obtained from this experiment will be
           compared with data obtained after injection of aspart insulin by conventional pen both
           in this study and in a previous investigation.

           The investigators will also ask the subject on both experimental days, within 30 minutes
           after insulin injection, to point out on a numeric rating scale from 0 to 10 the amount
           of discomfort or pain and the ease of use experienced with the two administration
           methods. After the second experiment day, patients will be asked which of the two
           devices they would prefer for insulin injection, should they have a choice.

           Withdrawal of study subjects Subjects can leave the study at any time for any reason if
           they wish to do so without any consequences. The investigator can decide to withdraw a
           subject from the study in case of a severe adverse event or another condition requiring
           immediate medical care. Appropriate follow up and treatment of withdrawn subjects will
           be assured. Every subject that withdraws from the study will be replaced with an
           additional study participant.

           Premature termination of the study The study will be terminated prematurely when
           unexpected serious adverse events are experienced which endanger other subjects. If the
           trial is prematurely terminated the investigator will promptly inform the trial
           subjects, the METC and competent authority. A detailed written explanation of the
           termination will be provided. Appropriate follow up and treatment of trial subjects will
           be assured.

        7. Safety reporting The investigator will inform the subjects and the reviewing accredited
           METC if anything occurs, on the basis of which it appears that the disadvantages of
           participation may be significantly greater than was foreseen in the research proposal.
           The study will be suspended pending further review by the accredited METC, except
           insofar as suspension would jeopardise the subjects' health. The investigator will take
           care that all subjects are kept informed. All (serious) adverse events reported
           spontaneously by the subject or observed by the investigator or his staff will be
           recorded and reported at the METC.

        8. Statistical analysis Descriptive parameters will be presented as mean ± standard error
           of the mean. Unpaired T-tests will be performed to compare all main and secondary study
           endpoints as well as most ease of use and safety endpoints. A Chi2 test will be used to
           compare the number of patients experiencing post injection hypoglycaemia with the two
           injection devices. A P-value of < 0.05 will be considered as statistically significant.
           All statistical analyses will be performed using SPSS 20.0 or higher.

        9. Administrative aspects, monitoring and publication The investigator will preserve
           confidentiality of all subjects taking part in the study, in accordance with GCP and
           local regulations. The investigator must ensure that the subjects anonymity is
           maintained. Al data and material from one individual subject will be coded by an unique
           identification code. The key to the code is maintained by the investigator and research
           nurses. The validated data management system Castor will be used for data handling,
           according to GCP. Data will be stored for 15 years. Human material will be stored for 10
           years. Source document and database verification will be performed by an independent
           monitor, according to a predefined monitoring plan. There will be minimal monitoring,
           once per year, as the study is judged to cause only marginal potential risk to the
           participants.

       10. Public disclosure and publication policy This study has been made possible by an
           unrestricted grant from European Pharma Group (EPG), division Needle Free Insulin
           Products, the manufacturer of the InsujetTM jet-injector. EPG was not involved in the
           study design or writing of the protocol and will also not be involved in conducting the
           study, analysis of the data, presentation of the results, writing of the manuscript and
           the decision to submit for publication.
    

Intervention name(s): jet injector; Conventional pen (NovoPen IV)
Intervention type(s): Device; Device
Intervention description(s): 1 administration of insulin in a dose of 0.2 units per kg body weight subcutaneously in the abdomen, 1 empty administration; 1 administration of insulin in a dose of 0.2 units per kg body weight subcutaneously in the abdomen, 1 empty administration
Other intervention name(s): Insujet™, European Pharma Group, The Netherlands; NovoPen IV, Novo Nordisk
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Injections, Jet; pharmacology; Insulin Aspart; Equipment and Supplies