Diabetes MellitusPhase 4NCT02272296

Reliability of Insulin by Jet Injection

A Phase 4 study testing jet injector and Conventional pen (NovoPen IV) in people with Diabetes Mellitus, run by Radboud University Medical Center at 1 site in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 50 yearsHealthy volunteers can take part
Conditions the study is for: Diabetes Mellitus
What is being tested?: jet injector and Conventional pen (NovoPen IV)
Type of treatment: Injection or infusion, Medical device
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 30 participants
Where: 1 siteNetherlands
Study dates: Feb 2015to Aug 2015
Phase: Phase 4
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 50 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

Age 18-50 years
Body-Mass Index 18-32 kg/m2
Blood pressure <160/90 mmHg

Who cannot join

Inability to provide informed consent
Chronic use of medication other than oral contraceptives or thyroid hormone replacement therapy (with stable euthyroidism for at least 3 months)
Treatment with systemic corticosteroids, immunosuppressive or cytostatic drugs
Known allergy to aspart insulin
History of a major cardiovascular disease event (myocardial infarction, stroke, symptomatic peripheral artery disease, coronary bypass surgery, percutaneous coronary or peripheral artery angioplasty) in the previous 6 months
Presence of any other medical condition that might interfere with the study protocol
Pregnancy or the intention to become pregnant
Anemia, defined as an Hb of <8.1 mmol/l for male subjects and <7.5 for female subjects

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

Radboud university medical center
Nijmegen, 6542 JK

Other trials in Netherlands

About this study

Official title: Reproducibility of Insulin Action When Administered by Needle-free Jet Injection

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

Read the detailed description

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Conditions: Diabetes Mellitus
Being tested: jet injector, Conventional pen (NovoPen IV)
Keywords: Injections, Jet, pharmacology, Insulin Aspart, Equipment and Supplies
Medical subject headings: Diabetes Mellitus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

jet injectorDevice
Also called Insujet™, European Pharma Group, The Netherlands
1 administration of insulin in a dose of 0.2 units per kg body weight subcutaneously in the abdomen, 1 empty administration
Conventional pen (NovoPen IV)Device
Also called NovoPen IV, Novo Nordisk
1 administration of insulin in a dose of 0.2 units per kg body weight subcutaneously in the abdomen, 1 empty administration

Study groups in NCT02272296
Study group	Role	What they receive
Jet Injector_main study	Active comparator	Administration of insulin or placebo injection in main study Receives: Device: jet injector; Device: Conventional pen (NovoPen IV)
conventional pen, NovoPen IV	Placebo comparator	Administration of insulin or placebo injection in main study Receives: Device: jet injector; Device: Conventional pen (NovoPen IV)
jet injector_sub study	Active comparator	Administration of insulin or placebo injection in sub study Receives: Device: jet injector

What is being measured

The primary outcome is the main question the study is designed to answer.

(TmaxGIR)
The variability in time until maximal glucose lowering effect, as determined by exogenous glucose requirement (TmaxGIR) to maintain normoglycemia, after insulin injection. Primary endpoint of main study
Measured: 0-6 hrs
Tmax (min)
Time to maximal exogenous glucose infusion rate (GIR, in ml/min/kg) required to maintain euglycaemia. Primary endpoint of sub study.
Measured: 0-6 hrs

Secondary outcomes (7)

CmaxGIR (mg/min)
Maximal GIR during the 6-hour study (from timepoint 0)
Measured: 0-6 hrs
CmaxINS (pmol/l)
Maximal insulin concentration during the 6-hour study (from timepoint 0)
Measured: 0-6 hrs
TmaxINS (min)
Time to maximal insulin concentration (Cmax)
Measured: 0-6 hrs
AUCINS (pmol/min/l)
area under the insulin concentration curve during the 6-hour study
Measured: 0-6 hrs
AUCGIR (g):
Area under the GIR curve during the 6-hour study (from timepoint 0)
Measured: 0-6 hrs
T-GIRAUC50% (min)
Time of 50% of glucose disposal, i.e. the median of the GIR profile
Measured: 0-6 hrs
T-INSAUC50% (min)
Time until 50% of insulin absorption (mean residence time, MRT)
Measured: 0-6 hrs

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Feb 2015Aug 2015

First posted22 Oct 2014 (estimated)
Study startFeb 2015
Primary completionAug 2015
Study completionAug 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (12)Papers the sponsor has linked to this study.
Other trials for Diabetes MellitusStudies of the same condition, open and under way.
More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Investigator, Outcomes assessor
Enrolment: 30 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02272296
Sponsor's protocol ID: PKPD_INSJ_4
Status last verified: Oct 2015
First submitted: 14 Oct 2014
Last updated: 28 Oct 2015
Results posted: No
Data monitoring committee: Yes

Publications

Mitragotri S. Current status and future prospects of needle-free liquid jet injectors. Nat Rev Drug Discov. 2006 Jul;5(7):543-8. doi: 10.1038/nrd2076.
PubMed 16816837
Malone JI, Lowitt S, Grove NP, Shah SC. Comparison of insulin levels after injection by jet stream and disposable insulin syringe. Diabetes Care. 1986 Nov-Dec;9(6):637-40. doi: 10.2337/diacare.9.6.637.
PubMed 3542456
Weller C, Linder M. Jet injection of insulin vs the syringe-and-needle method. JAMA. 1966 Mar 7;195(10):844-7. doi: 10.1001/jama.1966.03100100096027.
PubMed 12608170
Taylor R, Home PD, Alberti KG. Plasma free insulin profiles after administration of insulin by jet and conventional syringe injection. Diabetes Care. 1981 May-Jun;4(3):377-9. doi: 10.2337/diacare.4.3.377.
PubMed 7047114
Pehling GB, Gerich JE. Comparison of plasma insulin profiles after subcutaneous administration of insulin by jet spray and conventional needle injection in patients with insulin-dependent diabetes mellitus. Mayo Clin Proc. 1984 Nov;59(11):751-4. doi: 10.1016/s0025-6196(12)65585-2.
PubMed 6387316
Halle JP, Lambert J, Lindmayer I, Menassa K, Coutu F, Moghrabi A, Legendre L, Legault C, Lalumiere G. Twice-daily mixed regular and NPH insulin injections with new jet injector versus conventional syringes: pharmacokinetics of insulin absorption. Diabetes Care. 1986 May-Jun;9(3):279-82. doi: 10.2337/diacare.9.3.279.
PubMed 3525057
Kerum G, Profozic V, Granic M, Skrabalo Z. Blood glucose and free insulin levels after the administration of insulin by conventional syringe or jet injector in insulin treated type 2 diabetics. Horm Metab Res. 1987 Sep;19(9):422-5. doi: 10.1055/s-2007-1011842.
PubMed 3319860
Lucas A, Ribas L, Salinas I, Audi L, Sanmarti A, Foz M. Insulin levels after injection by jet stream and disposable syringe. Diabetes Care. 1988 Mar;11(3):298-9. doi: 10.2337/diacare.11.3.298a. No abstract available.
PubMed 3046856
Engwerda EE, Abbink EJ, Tack CJ, de Galan BE. Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology. Diabetes Care. 2011 Aug;34(8):1804-8. doi: 10.2337/dc11-0182. Epub 2011 Jun 29.
PubMed 21715522
Gill GV, Yudkin JS, Keen H, Beran D. The insulin dilemma in resource-limited countries. A way forward? Diabetologia. 2011 Jan;54(1):19-24. doi: 10.1007/s00125-010-1897-3. Epub 2010 Sep 12.
PubMed 20835860
Julious SA. Sample sizes for clinical trials with normal data. Stat Med. 2004 Jun 30;23(12):1921-86. doi: 10.1002/sim.1783.
PubMed 15195324
Engwerda EEC, Tack CJ, de Galan BE. Pharmacokinetic and Pharmacodynamic Variability of Insulin When Administered by Jet Injection. J Diabetes Sci Technol. 2017 Sep;11(5):947-952. doi: 10.1177/1932296817699638. Epub 2017 Mar 17.
PubMed 28303726

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 28 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Reproducibility of Insulin Action When Administered by Needle-free Jet Injection
ClinicalTrials.gov ID: NCT02272296
Acronym / sponsor ID: PKPD_INSJ_4
Conditions: Diabetes Mellitus
Keywords: Injections, Jet, pharmacology, Insulin Aspart, Equipment and Supplies
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 30 participants (actual)
Lead sponsor: Radboud University Medical CenterUniversity, hospital or other
Study start: Feb 2015
Primary completion: Aug 2015 (actual)
Study completion: Aug 2015 (actual)
First posted: 22 Oct 2014 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design: Double-blind double-dummy randomized controlled parallel/cross-over

Detailed description

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
Jet Injector_main study	Active comparator	Device: jet injector, Device: Conventional pen (NovoPen IV)Administration of insulin or placebo injection in main study
conventional pen, NovoPen IV	Placebo comparator	Device: jet injector, Device: Conventional pen (NovoPen IV)Administration of insulin or placebo injection in main study
jet injector_sub study	Active comparator	Device: jet injectorAdministration of insulin or placebo injection in sub study

Who may qualify

Ages: 18 to 50 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (3 listed)

Age 18-50 years
Body-Mass Index 18-32 kg/m2
Blood pressure <160/90 mmHg

Key exclusion criteria (8 listed)

Inability to provide informed consent
Chronic use of medication other than oral contraceptives or thyroid hormone replacement therapy (with stable euthyroidism for at least 3 months)
Treatment with systemic corticosteroids, immunosuppressive or cytostatic drugs
Known allergy to aspart insulin
History of a major cardiovascular disease event (myocardial infarction, stroke, symptomatic peripheral artery disease, coronary bypass surgery, percutaneous coronary or peripheral artery angioplasty) in the previous 6 months

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
jet injectorAlso: Insujet™, European Pharma Group, The Netherlands1 administration of insulin in a dose of 0.2 units per kg body weight subcutaneously in the abdomen, 1 empty administration	Device	Jet Injector_main study, conventional pen, NovoPen IV, jet injector_sub study
Conventional pen (NovoPen IV)Also: NovoPen IV, Novo Nordisk1 administration of insulin in a dose of 0.2 units per kg body weight subcutaneously in the abdomen, 1 empty administration	Device	Jet Injector_main study, conventional pen, NovoPen IV

Primary outcome

(TmaxGIR)
Time frame: 0-6 hrs
The variability in time until maximal glucose lowering effect, as determined by exogenous glucose requirement (TmaxGIR) to maintain normoglycemia, after insulin injection. Primary endpoint of main study
Tmax (min)
Time frame: 0-6 hrs
Time to maximal exogenous glucose infusion rate (GIR, in ml/min/kg) required to maintain euglycaemia. Primary endpoint of sub study.

7 secondary outcomes

CmaxGIR (mg/min)
Time frame: 0-6 hrs
CmaxINS (pmol/l)
Time frame: 0-6 hrs
TmaxINS (min)
Time frame: 0-6 hrs
AUCINS (pmol/min/l)
Time frame: 0-6 hrs
AUCGIR (g):
Time frame: 0-6 hrs
T-GIRAUC50% (min)
Time frame: 0-6 hrs
T-INSAUC50% (min)
Time frame: 0-6 hrs

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2015.
Background: PubMed 16816837Mitragotri S. Current status and future prospects of needle-free liquid jet injectors. Nat Rev Drug Discov. 2006 Jul;5(7):543-8. doi: 10.1038/nrd2076.
Background: PubMed 3542456Malone JI, Lowitt S, Grove NP, Shah SC. Comparison of insulin levels after injection by jet stream and disposable insulin syringe. Diabetes Care. 1986 Nov-Dec;9(6):637-40. doi: 10.2337/diacare.9.6.637.
Background: PubMed 12608170Weller C, Linder M. Jet injection of insulin vs the syringe-and-needle method. JAMA. 1966 Mar 7;195(10):844-7. doi: 10.1001/jama.1966.03100100096027.
Background: PubMed 7047114Taylor R, Home PD, Alberti KG. Plasma free insulin profiles after administration of insulin by jet and conventional syringe injection. Diabetes Care. 1981 May-Jun;4(3):377-9. doi: 10.2337/diacare.4.3.377.
Background: PubMed 6387316Pehling GB, Gerich JE. Comparison of plasma insulin profiles after subcutaneous administration of insulin by jet spray and conventional needle injection in patients with insulin-dependent diabetes mellitus. Mayo Clin Proc. 1984 Nov;59(11):751-4. doi: 10.1016/s0025-6196(12)65585-2.
Background: PubMed 3525057Halle JP, Lambert J, Lindmayer I, Menassa K, Coutu F, Moghrabi A, Legendre L, Legault C, Lalumiere G. Twice-daily mixed regular and NPH insulin injections with new jet injector versus conventional syringes: pharmacokinetics of insulin absorption. Diabetes Care. 1986 May-Jun;9(3):279-82. doi: 10.2337/diacare.9.3.279.
Background: PubMed 3319860Kerum G, Profozic V, Granic M, Skrabalo Z. Blood glucose and free insulin levels after the administration of insulin by conventional syringe or jet injector in insulin treated type 2 diabetics. Horm Metab Res. 1987 Sep;19(9):422-5. doi: 10.1055/s-2007-1011842.
Background: PubMed 3046856Lucas A, Ribas L, Salinas I, Audi L, Sanmarti A, Foz M. Insulin levels after injection by jet stream and disposable syringe. Diabetes Care. 1988 Mar;11(3):298-9. doi: 10.2337/diacare.11.3.298a. No abstract available.
Background: PubMed 21715522Engwerda EE, Abbink EJ, Tack CJ, de Galan BE. Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology. Diabetes Care. 2011 Aug;34(8):1804-8. doi: 10.2337/dc11-0182. Epub 2011 Jun 29.
Background: PubMed 20835860Gill GV, Yudkin JS, Keen H, Beran D. The insulin dilemma in resource-limited countries. A way forward? Diabetologia. 2011 Jan;54(1):19-24. doi: 10.1007/s00125-010-1897-3. Epub 2010 Sep 12.
Background: PubMed 15195324Julious SA. Sample sizes for clinical trials with normal data. Stat Med. 2004 Jun 30;23(12):1921-86. doi: 10.1002/sim.1783.
Derived from this study: PubMed 28303726Engwerda EEC, Tack CJ, de Galan BE. Pharmacokinetic and Pharmacodynamic Variability of Insulin When Administered by Jet Injection. J Diabetes Sci Technol. 2017 Sep;11(5):947-952. doi: 10.1177/1932296817699638. Epub 2017 Mar 17.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Bastiaan E de Galan, MD, PhD principal investigator

Radboud University Medical Center

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing jet injector and Conventional pen (NovoPen IV) in people with Diabetes Mellitus, run by Radboud University Medical Center at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

(TmaxGIR) (time frame: 0-6 hrs). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02272296, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2015.