Clinical trial NCT04414579: The Efficacy and Safety of Faster Insulin Aspart (Fiasp®) Compared to Conventional Insulin Aspart (NovoLog®) as Correction Bolus
Official title: The Efficacy and Safety of Faster Insulin Aspart (Fiasp®) Compared to Conventional Insulin Aspart (NovoLog®) as Correction Bolus in Patients With Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion (CSII) and Continuous Glucose Monitoring (CGM): a Cross-over Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Type 1 Diabetes Mellitus
Keywords: continuous glucose monitoring
continuous subcutaneous insulin infusion
hyperglycemia
correction bolus
Lead sponsor: Mountain Diabetes and Endocrine Center
Sponsor class: OTHER
First posted: 2020-06-04
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a 25-week open-label prospective single center 2 arm crossover trial consisting of a CSII settings (basal, bolus, and correction factors) will be optimized for a 2-week run in period followed by a 10-week period of CSII use with the assigned insulin. After a 12-week maintenance period, each group will cross over to the other insulin (conventional insulin aspart or Fiasp) by CSII for a second 2-week optimization period followed by a 10-week treatment period.
Primary purpose: TREATMENT

Brief summary: The purpose of this investigator-initiated trial is to compare the efficacy in terms of time to recovery from hyperglycemia as measured by time to arrest of hyperglycemic excursion ("glucose plateau point", primary endpoint) and return to premeal glucose target if feasible (secondary endpoint) between Fiasp and conventional insulin aspart when used as a correction bolus. These endpoints will be determined by CGM (Dexcom) from data exported from the Dexcom Clarity program.

Detailed description: Patients with type 1 DM using CSII require bolus insulin for two purposes: first, to cover carbohydrate intake to control postprandial glucose, and second, to correct episodes of hyperglycemia. The latter function is referred to as a "correction dose" or "correction bolus". Insulin pumps have bolus calculators which calculate correction doses based on the patient's individualized BG target and insulin sensitivity factor (ISF). Rapid-acting insulin analogues delivered by pump typically require 2 to 4 hours to fully correct an acute hyperglycemic episode, and sometimes multiple correction doses are needed to normalize the blood glucose level. This can be frustrating for patients, particularly when a correction bolus is necessary in addition to a meal bolus; frequently, patients must wait for the correction bolus to take effect and delay eating until the blood glucose has begun to normalize to avoid severe postprandial hyperglycemia. There is consequently an unmet need in insulin delivery, and in particular in CSII, for an insulin which can correct a hyperglycemic episode more rapidly than is currently possible with rapid-acting insulin analogues.

Faster insulin aspart (Fiasp) is a novel formulation of insulin aspart with an accelerated time-action profile which results in twice the exposure to insulin and 74% greater insulin action within the first 30 minutes after injection compared to conventional insulin aspart. This results in twice-as-fast onset of appearance in the bloodstream (4 vs. 9 min compared to conventional insulin aspart) which has been demonstrated to reduce postprandial glucose levels in patients with type 1 DM using CSII. Theoretically, this faster insulin action would be useful in correction dosing during acute episodes of hyperglycemia to normalize the blood glucose level more rapidly than is currently possible with conventional insulin aspart (NovoLog).

Many patients with type 1 DM using CSII now also use continuous glucose monitoring (CGM) for making insulin dosing decisions. Currently the FDA has approved 2 CGM systems for nonadjunctive use in bolus insulin dose calculations. Only one of these systems, the Dexcom, reads continuously to the patient and has alarms to warn of impending episodes of hyper- or hypoglycemia, and this is the system used most commonly by patients with type 1 DM using open-loop CSII. Patients now incorporate the Dexcom trend arrow, which depicts the rate and direction of glucose change, into the correction dose calculation, and recommendations on how to incorporate CGM information into correction dose calculations have recently been updated based on an expert consensus report. However, these guidelines were created for use with rapid acting insulin analogues. How they might need to be modified for use with Fiasp (the first and only ultra-rapid insulin analogue) is not known.

The purpose of this investigator-initiated trial is to compare the efficacy in terms of time to recovery from hyperglycemia as measured by time to arrest of hyperglycemic excursion ("glucose plateau point", primary endpoint) and return to premeal glucose target if feasible (secondary endpoint) between Fiasp and conventional insulin aspart when used as a correction bolus. These endpoints will be determined by CGM (Dexcom) from data exported from the Dexcom Clarity program.

Study hypothesis:

Compared to conventional insulin aspart, Fiasp will correct hyperglycemia (defined as arrest of rise of blood glucose, following correction bolus, ie, GPP ) faster than conventional insulin aspart in subjects with type 1 DM using CSII.

Eligibility criteria: Inclusion Criteria:

* Male and female patients \> 18 years of age
* Type 1 DM of \> 1 year duration
* Use of any open loop insulin pump, Tandem T-Slim with Basal IQ, Insulet Omnipod Dash, or any other investigator-approved insulin pumps with Dexcom CGM G5, G6, or newer version for \> 6 months
* Good baseline glycemic control (HbA1c \< 7.5%; low risk of hypoglycemia by CGM as defined by Dexcom Clarity report)
* No episodes of severe hypoglycemia in the previous 3 months
* Pump download shows regular meal bolusing, accurate carbohydrate counting ability, and willingness to use exercise markers in Dexcom
* CGM download shows regular use (\>85% of time) and regular calibration if using G5 sensor (G6 requires no calibration)
* Females using adequate contraception

Exclusion Criteria:

* Use of CGM other than Dexcom G5 or G6 or a newer Dexcom CGM version
* Suboptimal baseline glycemic control (HbA1c \> 7.5%)
* Pump or CGM download shows suboptimal use of devices (lack of meal boluses, frequent overrides of pump, excessive pump suspension, inadequate calibration or inconsistent usage of CGM)
* Serious comorbidities including CVD with recent event, actively treated malignancy, renal dysfunction with eGFR \< 45 ml/min, or any other condition which in the opinion of the investigator would preclude subject's ability to participate in trial
* Females unwilling to use contraception, planning pregnancy or breastfeeding
* Use of any other glucose-lowering agents than insulin
* Hypersensitivity to insulin aspart or one of the excipients in faster insulin aspart
* Known diabetic gastroparesis

Primary outcomes:
measure: Time to stabilization of rising blood sugar by CGM after correction bolus
timeFrame: 2 weeks
Secondary outcomes:
measure: Incidence of early hypoglycemia
timeFrame: 25 weeks
measure: Change in Insulin Sensitivity Factor
timeFrame: 25 weeks
measure: Change in Insulin On Board
timeFrame: 25 weeks
measure: GlycoMark differences between arms
timeFrame: 25 weeks
measure: HbA1c differences between arms
timeFrame: 25 weeks
measure: Percent time spent in target range, hyperglycemic range, and hypoglycemic range
timeFrame: 4 weeks
measure: Standard deviation differences between arms
timeFrame: 4 weeks
measure: Treatment related impact measures between arms
timeFrame: 6 weeks
Other outcomes:
Locations:
city: Asheville
country: United States
facility: Mountain Diabetes and Endocrine Center
state: North Carolina
Study officials:
References:
citation: Bode BW, Johnson JA, Hyveled L, Tamer SC, Demissie M. Improved Postprandial Glycemic Control with Faster-Acting Insulin Aspart in Patients with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion. Diabetes Technol Ther. 2017 Jan;19(1):25-33. doi: 10.1089/dia.2016.0350. Epub 2017 Jan 5.
citation: Aleppo G, Laffel LM, Ahmann AJ, Hirsch IB, Kruger DF, Peters A, Weinstock RS, Harris DR. A Practical Approach to Using Trend Arrows on the Dexcom G5 CGM System for the Management of Adults With Diabetes. J Endocr Soc. 2017 Nov 20;1(12):1445-1460. doi: 10.1210/js.2017-00388. eCollection 2017 Dec 1.
citation: Heise T, Pieber TR, Danne T, Erichsen L, Haahr H. A Pooled Analysis of Clinical Pharmacology Trials Investigating the Pharmacokinetic and Pharmacodynamic Characteristics of Fast-Acting Insulin Aspart in Adults with Type 1 Diabetes. Clin Pharmacokinet. 2017 May;56(5):551-559. doi: 10.1007/s40262-017-0514-8.
citation: Russell-Jones D, Bode BW, De Block C, Franek E, Heller SR, Mathieu C, Philis-Tsimikas A, Rose L, Woo VC, Osterskov AB, Graungaard T, Bergenstal RM. Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1). Diabetes Care. 2017 Jul;40(7):943-950. doi: 10.2337/dc16-1771. Epub 2017 Mar 29.
citation: Bergenstal RM, Garg S, Weinzimer SA, Buckingham BA, Bode BW, Tamborlane WV, Kaufman FR. Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes. JAMA. 2016 Oct 4;316(13):1407-1408. doi: 10.1001/jama.2016.11708. No abstract available.
citation: Klonoff DC, Evans ML, Lane W, Kempe HP, Renard E, DeVries JH, Graungaard T, Hyseni A, Gondolf T, Battelino T. A randomized, multicentre trial evaluating the efficacy and safety of fast-acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5). Diabetes Obes Metab. 2019 Apr;21(4):961-967. doi: 10.1111/dom.13610. Epub 2019 Jan 13.