<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04414579</url>
  </required_header>
  <id_info>
    <org_study_id>GPP2019</org_study_id>
    <nct_id>NCT04414579</nct_id>
  </id_info>
  <brief_title>The Efficacy and Safety of Faster Insulin Aspart (Fiasp®) Compared to Conventional Insulin Aspart (NovoLog®) as Correction Bolus</brief_title>
  <acronym>PLATEAU</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mountain Diabetes and Endocrine Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mountain Diabetes and Endocrine Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this investigator-initiated trial is to compare the efficacy in terms of time&#xD;
      to recovery from hyperglycemia as measured by time to arrest of hyperglycemic excursion&#xD;
      (&quot;glucose plateau point&quot;, primary endpoint) and return to premeal glucose target if feasible&#xD;
      (secondary endpoint) between Fiasp and conventional insulin aspart when used as a correction&#xD;
      bolus. These endpoints will be determined by CGM (Dexcom) from data exported from the Dexcom&#xD;
      Clarity program.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with type 1 DM using CSII require bolus insulin for two purposes: first, to cover&#xD;
      carbohydrate intake to control postprandial glucose, and second, to correct episodes of&#xD;
      hyperglycemia. The latter function is referred to as a &quot;correction dose&quot; or &quot;correction&#xD;
      bolus&quot;. Insulin pumps have bolus calculators which calculate correction doses based on the&#xD;
      patient's individualized BG target and insulin sensitivity factor (ISF). Rapid-acting insulin&#xD;
      analogues delivered by pump typically require 2 to 4 hours to fully correct an acute&#xD;
      hyperglycemic episode, and sometimes multiple correction doses are needed to normalize the&#xD;
      blood glucose level. This can be frustrating for patients, particularly when a correction&#xD;
      bolus is necessary in addition to a meal bolus; frequently, patients must wait for the&#xD;
      correction bolus to take effect and delay eating until the blood glucose has begun to&#xD;
      normalize to avoid severe postprandial hyperglycemia. There is consequently an unmet need in&#xD;
      insulin delivery, and in particular in CSII, for an insulin which can correct a hyperglycemic&#xD;
      episode more rapidly than is currently possible with rapid-acting insulin analogues.&#xD;
&#xD;
      Faster insulin aspart (Fiasp) is a novel formulation of insulin aspart with an accelerated&#xD;
      time-action profile which results in twice the exposure to insulin and 74% greater insulin&#xD;
      action within the first 30 minutes after injection compared to conventional insulin aspart.&#xD;
      This results in twice-as-fast onset of appearance in the bloodstream (4 vs. 9 min compared to&#xD;
      conventional insulin aspart) which has been demonstrated to reduce postprandial glucose&#xD;
      levels in patients with type 1 DM using CSII. Theoretically, this faster insulin action would&#xD;
      be useful in correction dosing during acute episodes of hyperglycemia to normalize the blood&#xD;
      glucose level more rapidly than is currently possible with conventional insulin aspart&#xD;
      (NovoLog).&#xD;
&#xD;
      Many patients with type 1 DM using CSII now also use continuous glucose monitoring (CGM) for&#xD;
      making insulin dosing decisions. Currently the FDA has approved 2 CGM systems for&#xD;
      nonadjunctive use in bolus insulin dose calculations. Only one of these systems, the Dexcom,&#xD;
      reads continuously to the patient and has alarms to warn of impending episodes of hyper- or&#xD;
      hypoglycemia, and this is the system used most commonly by patients with type 1 DM using&#xD;
      open-loop CSII. Patients now incorporate the Dexcom trend arrow, which depicts the rate and&#xD;
      direction of glucose change, into the correction dose calculation, and recommendations on how&#xD;
      to incorporate CGM information into correction dose calculations have recently been updated&#xD;
      based on an expert consensus report. However, these guidelines were created for use with&#xD;
      rapid acting insulin analogues. How they might need to be modified for use with Fiasp (the&#xD;
      first and only ultra-rapid insulin analogue) is not known.&#xD;
&#xD;
      The purpose of this investigator-initiated trial is to compare the efficacy in terms of time&#xD;
      to recovery from hyperglycemia as measured by time to arrest of hyperglycemic excursion&#xD;
      (&quot;glucose plateau point&quot;, primary endpoint) and return to premeal glucose target if feasible&#xD;
      (secondary endpoint) between Fiasp and conventional insulin aspart when used as a correction&#xD;
      bolus. These endpoints will be determined by CGM (Dexcom) from data exported from the Dexcom&#xD;
      Clarity program.&#xD;
&#xD;
      Study hypothesis:&#xD;
&#xD;
      Compared to conventional insulin aspart, Fiasp will correct hyperglycemia (defined as arrest&#xD;
      of rise of blood glucose, following correction bolus, ie, GPP ) faster than conventional&#xD;
      insulin aspart in subjects with type 1 DM using CSII.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">March 27, 2019</start_date>
  <completion_date type="Anticipated">March 2021</completion_date>
  <primary_completion_date type="Anticipated">March 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>This is an open-label crossover trial. Subjects will be randomized to treatment sequence (Fiasp then NovoLog or NovoLog then Fiasp), each for a 12-week treatment period, by CSII. Randomization sequence will be determined by computerized randomization program. All patients will receive both treatments unless they drop out. Dropouts are unlikely since the participants are all regular continuing patients of the site's clinical practice.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time to stabilization of rising blood sugar by CGM after correction bolus</measure>
    <time_frame>2 weeks</time_frame>
    <description>Time (in minutes) to stabilization of rising blood sugar (GPP) by CGM after correction bolus during the final 2 week maintenance period. Two categories of correction dose will be analyzed: 1) those following an isolated correction dose (taken independently of a meal dose), and 2) those taken as part of a combination bolus with a meal dose.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of early hypoglycemia</measure>
    <time_frame>25 weeks</time_frame>
    <description>Incidence of early hypoglycemia (Blood glucose &lt; 54 mg/dl within 1 and 2 hours) following correction bolus with each insulin (Key Safety Endpoint)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Insulin Sensitivity Factor</measure>
    <time_frame>25 weeks</time_frame>
    <description>Change in Insulin Sensitivity Factor, if any, required for hypoglycemia prevention using Fiasp as recorded by continuous subcutaneous insulin infusion device setting report</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Insulin On Board</measure>
    <time_frame>25 weeks</time_frame>
    <description>Change in Insulin On Board, if any, required for prevention of late hyperglycemia using Fiasp as recorded by continuous subcutaneous insulin infusion device setting report</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GlycoMark differences between arms</measure>
    <time_frame>25 weeks</time_frame>
    <description>GlycoMark (1,5 anhydroglucitol, a marker of postprandial glucose excursion) during use of each insulin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HbA1c differences between arms</measure>
    <time_frame>25 weeks</time_frame>
    <description>HbA1c during use of each insulin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent time spent in target range, hyperglycemic range, and hypoglycemic range</measure>
    <time_frame>4 weeks</time_frame>
    <description>Percent time spent in target range, hyperglycemic range and hypoglycemic range by Continuous Glucose Monitoring (CGM) on each insulin during the final 2 weeks of each treatment period. Target ranges include 70-180 mg/dL. Hyperglycemia ranges to be captured will include Category 1: 181-250 mg/dL and Category 2: above 250 mg/dL. Hypoglycemia ranges to be captured include Category 1: 69-54 mg/dL and Category 2: below 54 mg/dL.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Standard deviation differences between arms</measure>
    <time_frame>4 weeks</time_frame>
    <description>Standard deviation of mean blood glucose as determined by CGM on each insulin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment related impact measures between arms</measure>
    <time_frame>6 weeks</time_frame>
    <description>Treatment related impact measures on each insulin using TRIM D questionnaire</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">45</enrollment>
  <condition>Type 1 Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>No Intervention: Conventional Insulin Aspart (NovoLog®)</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>In the aspart group, the subject will only take aspart through the their pump. This study population will have an established expertise in diabetes self-management with previous knowledge of insulin pump therapy and Dexcom Continuous Glucose Monitoring (CGM). Allowing the subjects to use their insulin pumps for bolus insulin delivery, as they are accustomed, will minimize the chances of skipping meal boluses and correction doses. Aspart is put into their pump and delivered to their body through a small tube placed under your skin. In this NovoLog®-only treatment group, the subject will take aspart with each meal while your pump also gives you a slow, continuous dose of aspart for basal insulin. This treatment group is very similar (or even identical) to the treatment the subject was receiving prior to starting the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Faster Insulin Aspart (Fiasp®)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the Fiasp group, the subject will only take aspart through the their pump. This study population will have an established expertise in diabetes self-management with previous knowledge of insulin pump therapy and Dexcom Continuous Glucose Monitoring (CGM). Allowing the subjects to use their insulin pumps for bolus insulin delivery, as they are accustomed, will minimize the chances of skipping meal boluses and correction doses. Fiasp is put into their pump and delivered to their body through a small tube placed under their skin. In this Fiasp treatment group, the subject will take fiasp with each meal while their pump also gives them a slow, continuous dose of aspart for basal insulin. This treatment group is very similar (or even identical) to the treatment the subject was receiving prior to starting the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Faster Insulin Aspart (Fiasp®)</intervention_name>
    <description>Subjects will be randomized either to use Fiasp or conventional insulin aspart in CSII. CSII settings (basal, bolus, and correction factors) will be optimized using a meal challenge 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.</description>
    <arm_group_label>Faster Insulin Aspart (Fiasp®)</arm_group_label>
    <other_name>Conventional Insulin Aspart (NovoLog®)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female patients &gt; 18 years of age&#xD;
&#xD;
          -  Type 1 DM of &gt; 1 year duration&#xD;
&#xD;
          -  Use of any open loop insulin pump, Tandem T-Slim with Basal IQ, Insulet Omnipod Dash,&#xD;
             or any other investigator-approved insulin pumps with Dexcom CGM G5, G6, or newer&#xD;
             version for &gt; 6 months&#xD;
&#xD;
          -  Good baseline glycemic control (HbA1c &lt; 7.5%; low risk of hypoglycemia by CGM as&#xD;
             defined by Dexcom Clarity report)&#xD;
&#xD;
          -  No episodes of severe hypoglycemia in the previous 3 months&#xD;
&#xD;
          -  Pump download shows regular meal bolusing, accurate carbohydrate counting ability, and&#xD;
             willingness to use exercise markers in Dexcom&#xD;
&#xD;
          -  CGM download shows regular use (&gt;85% of time) and regular calibration if using G5&#xD;
             sensor (G6 requires no calibration)&#xD;
&#xD;
          -  Females using adequate contraception&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of CGM other than Dexcom G5 or G6 or a newer Dexcom CGM version&#xD;
&#xD;
          -  Suboptimal baseline glycemic control (HbA1c &gt; 7.5%)&#xD;
&#xD;
          -  Pump or CGM download shows suboptimal use of devices (lack of meal boluses, frequent&#xD;
             overrides of pump, excessive pump suspension, inadequate calibration or inconsistent&#xD;
             usage of CGM)&#xD;
&#xD;
          -  Serious comorbidities including CVD with recent event, actively treated malignancy,&#xD;
             renal dysfunction with eGFR &lt; 45 ml/min, or any other condition which in the opinion&#xD;
             of the investigator would preclude subject's ability to participate in trial&#xD;
&#xD;
          -  Females unwilling to use contraception, planning pregnancy or breastfeeding&#xD;
&#xD;
          -  Use of any other glucose-lowering agents than insulin&#xD;
&#xD;
          -  Hypersensitivity to insulin aspart or one of the excipients in faster insulin aspart&#xD;
&#xD;
          -  Known diabetic gastroparesis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Wendy S Lane, MD</last_name>
    <phone>8286849588</phone>
    <email>mountaindiabetes@msn.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Melinda L Buford, RN, BSN</last_name>
    <phone>8286849588</phone>
    <phone_ext>314</phone_ext>
    <email>mbuford@mdecresearch.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Mountain Diabetes and Endocrine Center</name>
      <address>
        <city>Asheville</city>
        <state>North Carolina</state>
        <zip>28803</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melinda L Buford, RN, BSN</last_name>
      <phone>828-684-9588</phone>
      <phone_ext>314</phone_ext>
      <email>mbuford@mdecresearch.com</email>
    </contact>
    <investigator>
      <last_name>Stephen L Weinrib, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Lynn L Baru, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Michael D Skrzynski, ANP</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <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>
    <PMID>28055230</PMID>
  </reference>
  <reference>
    <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>
    <PMID>29344577</PMID>
  </reference>
  <reference>
    <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>
    <PMID>28205039</PMID>
  </reference>
  <reference>
    <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>
    <PMID>28356319</PMID>
  </reference>
  <reference>
    <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>
    <PMID>27629148</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>30537180</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>May 26, 2020</study_first_submitted>
  <study_first_submitted_qc>May 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>November 20, 2020</last_update_submitted>
  <last_update_submitted_qc>November 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mountain Diabetes and Endocrine Center</investigator_affiliation>
    <investigator_full_name>Wendy Lane MD</investigator_full_name>
    <investigator_title>Wendy Lane, MD, Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>continuous glucose monitoring</keyword>
  <keyword>continuous subcutaneous insulin infusion</keyword>
  <keyword>hyperglycemia</keyword>
  <keyword>correction bolus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin</mesh_term>
    <mesh_term>Insulin, Globin Zinc</mesh_term>
    <mesh_term>Insulin Aspart</mesh_term>
    <mesh_term>Insulin, Long-Acting</mesh_term>
    <mesh_term>Insulin degludec, insulin aspart drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data and statistical analysis will be available to any researcher with appropriate request</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>post-study, up to 5 years</ipd_time_frame>
    <ipd_access_criteria>email Principal Investigator</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 7, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT04414579/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04414579
org study id: GPP2019
nct id: NCT04414579
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
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
masking: None (Open Label)
masking description: This is an open-label crossover trial. Subjects will be randomized to treatment sequence (Fiasp then NovoLog or NovoLog then Fiasp), each for a 12-week treatment period, by CSII. Randomization sequence will be determined by computerized randomization program. All patients will receive both treatments unless they drop out. Dropouts are unlikely since the participants are all regular continuing patients of the site's clinical practice.
measure: Time to stabilization of rising blood sugar by CGM after correction bolus
time frame: 2 weeks
description: Time (in minutes) to stabilization of rising blood sugar (GPP) by CGM after correction bolus during the final 2 week maintenance period. Two categories of correction dose will be analyzed: 1) those following an isolated correction dose (taken independently of a meal dose), and 2) those taken as part of a combination bolus with a meal dose.
measure: Incidence of early hypoglycemia
time frame: 25 weeks
description: Incidence of early hypoglycemia (Blood glucose < 54 mg/dl within 1 and 2 hours) following correction bolus with each insulin (Key Safety Endpoint)
measure: Change in Insulin Sensitivity Factor
time frame: 25 weeks
description: Change in Insulin Sensitivity Factor, if any, required for hypoglycemia prevention using Fiasp as recorded by continuous subcutaneous insulin infusion device setting report
measure: Change in Insulin On Board
time frame: 25 weeks
description: Change in Insulin On Board, if any, required for prevention of late hyperglycemia using Fiasp as recorded by continuous subcutaneous insulin infusion device setting report
measure: GlycoMark differences between arms
time frame: 25 weeks
description: GlycoMark (1,5 anhydroglucitol, a marker of postprandial glucose excursion) during use of each insulin.
measure: HbA1c differences between arms
time frame: 25 weeks
description: HbA1c during use of each insulin
measure: Percent time spent in target range, hyperglycemic range, and hypoglycemic range
time frame: 4 weeks
description: Percent time spent in target range, hyperglycemic range and hypoglycemic range by Continuous Glucose Monitoring (CGM) on each insulin during the final 2 weeks of each treatment period. Target ranges include 70-180 mg/dL. Hyperglycemia ranges to be captured will include Category 1: 181-250 mg/dL and Category 2: above 250 mg/dL. Hypoglycemia ranges to be captured include Category 1: 69-54 mg/dL and Category 2: below 54 mg/dL.
measure: Standard deviation differences between arms
time frame: 4 weeks
description: Standard deviation of mean blood glucose as determined by CGM on each insulin
measure: Treatment related impact measures between arms
time frame: 6 weeks
description: Treatment related impact measures on each insulin using TRIM D questionnaire
arm group label: No Intervention: Conventional Insulin Aspart (NovoLog®)
arm group type: No Intervention
description: In the aspart group, the subject will only take aspart through the their pump. This study population will have an established expertise in diabetes self-management with previous knowledge of insulin pump therapy and Dexcom Continuous Glucose Monitoring (CGM). Allowing the subjects to use their insulin pumps for bolus insulin delivery, as they are accustomed, will minimize the chances of skipping meal boluses and correction doses. Aspart is put into their pump and delivered to their body through a small tube placed under your skin. In this NovoLog®-only treatment group, the subject will take aspart with each meal while your pump also gives you a slow, continuous dose of aspart for basal insulin. This treatment group is very similar (or even identical) to the treatment the subject was receiving prior to starting the study.
arm group label: Faster Insulin Aspart (Fiasp®)
arm group type: Active Comparator
description: In the Fiasp group, the subject will only take aspart through the their pump. This study population will have an established expertise in diabetes self-management with previous knowledge of insulin pump therapy and Dexcom Continuous Glucose Monitoring (CGM). Allowing the subjects to use their insulin pumps for bolus insulin delivery, as they are accustomed, will minimize the chances of skipping meal boluses and correction doses. Fiasp is put into their pump and delivered to their body through a small tube placed under their skin. In this Fiasp treatment group, the subject will take fiasp with each meal while their pump also gives them a slow, continuous dose of aspart for basal insulin. This treatment group is very similar (or even identical) to the treatment the subject was receiving prior to starting the study.
intervention type: Drug
intervention name: Faster Insulin Aspart (Fiasp®)
description: Subjects will be randomized either to use Fiasp or conventional insulin aspart in CSII. CSII settings (basal, bolus, and correction factors) will be optimized using a meal challenge 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.
arm group label: Faster Insulin Aspart (Fiasp®)
other name: Conventional Insulin Aspart (NovoLog®)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wendy S Lane, MD
phone: 8286849588
email: mountaindiabetes@msn.com
last name: Melinda L Buford, RN, BSN
phone: 8286849588
phone ext: 314
email: mbuford@mdecresearch.com
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
country: United States
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.
PMID: 28055230
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.
PMID: 29344577
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.
PMID: 28205039
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.
PMID: 28356319
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.
PMID: 27629148
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.
PMID: 30537180
responsible party type: Principal Investigator
investigator affiliation: Mountain Diabetes and Endocrine Center
investigator full name: Wendy Lane MD
investigator title: Wendy Lane, MD, Principal Investigator
mesh term: Diabetes Mellitus, Type 1
mesh term: Insulin
mesh term: Insulin, Globin Zinc
mesh term: Insulin Aspart
mesh term: Insulin, Long-Acting
mesh term: Insulin degludec, insulin aspart drug combination
sharing ipd: Yes
ipd description: Data and statistical analysis will be available to any researcher with appropriate request
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: post-study, up to 5 years
ipd access criteria: email Principal Investigator
provided document: 