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Study of HDV Insulin Versus Insulin in Type 1 Diabetes Subjects (ISLE-1) (ISLE-1)

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ClinicalTrials.gov Identifier: NCT02794155
Recruitment Status : Completed
First Posted : June 8, 2016
Last Update Posted : July 31, 2018
Sponsor:
Collaborator:
Integrium
Information provided by (Responsible Party):
Diasome Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE May 16, 2016
First Posted Date  ICMJE June 8, 2016
Last Update Posted Date July 31, 2018
Study Start Date  ICMJE June 2016
Actual Primary Completion Date April 28, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 3, 2016)
Change in HbA1c [ Time Frame: 26 weeks ]
Change in HbA1c from Week 0 to Week 13, from Week 0 to Week 26, and from Week 13 to Week 26
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 3, 2016)
  • Change in fasting blood glucose glucose levels [ Time Frame: 26 weeks ]
    Difference in fasting blood glucose levels Mean Mixed Tolerance Test AUC,
  • Hypoglycemia occurrences by category: Severe, Documented Symptomatic, and Asymptomatic Hypoglycemia [ Time Frame: 26 weeks ]
    Comparison of frequency and severity of hypoglycemia
  • Number of Patients with Adverse Events [ Time Frame: 26 weeks ]
    • To demonstrate the safety of HDV insulin lispro over 26 weeks of administration.
  • Change in total insulin usage [ Time Frame: 26 weeks ]
    • Comparison of basal and bolus insulin doses as a mean of 3 days of use at Week 0 and at 13 and 26 weeks, and comparison of total bolus insulin dosing at end of run-in phase to the end of the 13 week treatment period, and from the 13 week treatment period to the 26 week treatment period.
  • Change in Body Weight [ Time Frame: 26 weeks ]
    Comparison of change in body weight (in Kilograms) from baseline through week 26.
  • Mean Mixed Meal Tolerance Test [ Time Frame: 13 and 26 weeks ]
    Comparison of mean mixed meal tolerance test (MMTT) (AUC0-120) from Week 0 (baseline) to Week 13, from Week 0 (baseline) to Week 26, and from Week 13 to Week 26
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of HDV Insulin Versus Insulin in Type 1 Diabetes Subjects (ISLE-1)
Official Title  ICMJE Phase 2b, Multicenter, Randomized, Double Blind, Titration Trial for Efficacy and Safety of HDV Insulin Lispro in Combination With a Basal Insulin Versus Insulin Lispro in Combination With a Basal Insulin in Patients With Type 1 Diabetes
Brief Summary This will be a Phase 2b, multicenter, randomized, double blind, titration clinical study, evaluating the efficacy and safety in the HDV Insulin Lispro Group versus Insulin Lispro Group in patients with type 1 diabetes over a 26 week treatment period. The patients will be randomized using a centrally allocated randomization scheme to 1 of the 2 treatment arms in an overall 2:1 scheme (HDV Insulin Lispro: Insulin Lispro). Both arms will receive the randomized treatment in combination with glargine or detemir. Goal to demonstrate that the efficacy of HDV insulin lispro administered in combination with a basal insulin (HDV Insulin Lispro group) is non-inferior to insulin lispro in combination with a basal insulin (Insulin Lispro group), in effects on glycated hemoglobin (HbA1c) in patients with type 1 diabetes. If non-inferiority is demonstrated, confirm that HDV insulin lispro in combination with a basal insulin (HDV Insulin Lispro group) is superior to insulin lispro in combination with a basal insulin (Insulin Lispro group), in effects on HbA1c in patients with type 1 diabetes (≥ 0.4% decrease in HbA1c).
Detailed Description

This will be a Phase 2b, multicenter, randomized, double blind, titration clinical study, evaluating the efficacy and safety in the HDV Insulin Lispro Group versus Insulin Lispro Group in patients with type 1 diabetes over a 26 week treatment period. The patients will be randomized using a centrally allocated randomization scheme to 1 of the 2 treatment arms in an overall 2:1 scheme (HDV Insulin Lispro: Insulin Lispro). Both arms will receive the randomized treatment in combination with glargine or detemir.

SCREENING (Visit 1, Week -4 to -1) Patients will arrive for Screening following an 8 hour fast. During Screening, patients will sign the informed consent form, be reviewed for inclusion/exclusion, and provide medical history, concomitant medications, and demographics. They will have a brief physical exam and provide vital signs. Safety hematology/chemistry/urinalysis (with liver enzymes) will include infectious serology, and serum pregnancy test for women of childbearing potential. An ECG will be performed and patients will provide samples for HbA1c determination.

Patients taking lispro/glargine or lispro/detemir at the time of Screening and who meet all eligibility criteria will proceed to Visit 2 (Week -1).

TREATMENT PERIOD Visit 1a (Week -2) will be required only if a patient must convert to lispro prior to Visit 3 (Week 0, randomization). Patients taking non-lispro/glargine or non-lispro/detemir or using an insulin pump will be converted to lispro/glargine or lispro/detemir (respectively) using equivalent insulin units, then proceed to Visit 2 (Week -1) after 1 week on the new regimen. At Visit 2 (Week -1), patients will receive the CGM and be trained on its use. Patients will also have their first Mixed Meal Tolerance Test (MMTT) during Visit 2 (Week -1) accompanied by monitoring of blood ketones pre- and post-ingestion. CGM and MMTT will be repeated at Visits 9 (Week 12) and 14 (Week 25). A diary, glucose meter, and supplies will also be provided at Visit 2 (Week -1). Patients will be instructed on how to perform self-monitored blood glucose measurements (SMBG). During Visit 3 (Week 0), eligible patients will be randomized by IWRS to either treatment arm (Test Group or Control Group) and baseline data will be collected. All visits will include progress reviews and safety procedures. Safety hematology/chemistry/ urinalysis at Visits 2 (Week -1), 10 (Week 13), 14 (Week 25) and 16 (Week 27) will include liver enzymes. At Visits 6 (Week 5) and 12 (Week 19), liver enzymes will be the only chemistry safety tests performed. The only chemistry safety tests performed at Visits 2 (Week -1), 9 (Week 12), and 14 (Week 25) will be blood ketones; these will be measured at baseline and 3 hours after the MMTT. HbA1c will be measured at Visits 3 (Week 0), 4 (Week 1), 7 (Week 7), 10 (Week 13), 12 (Week 19), and 15 (Week 26). Fasting blood glucose will be measured at Visits 3 (Week 0), 10 (Week 13), and 15 (Week 26). An in-clinic urine pregnancy test will be performed at all visits for women of childbearing potential. MRI will be performed at Visits 3 (Week 0) and 14 (Week 25) for approximately 20% of patients in each treatment arm. MRI may also be performed on a case-by-case basis in the event of abnormal liver enzyme results. Patients will receive weekly telephone calls from the PI or a designee to discuss insulin dosing and titration.

FOLLOW-UP Visit 16 (Week 27) is a safety follow-up visit which will include a physical exam. Safety hematology/chemistry/ urinalysis (including liver enzymes) will include a urine pregnancy test for women of childbearing potential.

Concomitant medications, vital signs, and adverse events will be recorded throughout the entire study period.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Type 1 Diabetes Mellitus
Intervention  ICMJE
  • Drug: HDV Insulin Lispro
    HDV Insulin Lispro: ~1% of the Insulin Lispro is bound to HDV (Hepatocyte Directed Vesicle)
    Other Name: HDV Humalog
  • Drug: Insulin LISPRO
    Insulin Lispro: no bound insulin
    Other Name: Humalog
Study Arms  ICMJE
  • Experimental: Test Group
    HDV Insulin Lispro subcutaneous, pre-prandial dosing, 26 week treatment period
    Intervention: Drug: HDV Insulin Lispro
  • Active Comparator: Control Group
    Insulin Lispro subcutaneous, Pre-prandial dosing, 26 week treatment period
    Intervention: Drug: Insulin LISPRO
Publications * Klonoff D, Bode B, Cohen N, Penn M, Geho WB, Muchmore DB. Divergent Hypoglycemic Effects of Hepatic-Directed Prandial Insulin: A 6-Month Phase 2b Study in Type 1 Diabetes. Diabetes Care. 2019 Nov;42(11):2154-2157. doi: 10.2337/dc19-0152. Epub 2019 Sep 24.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 8, 2017)
157
Original Estimated Enrollment  ICMJE
 (submitted: June 3, 2016)
150
Actual Study Completion Date  ICMJE June 15, 2018
Actual Primary Completion Date April 28, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Men and women ≥ 18 yrs. of age
  2. Clinical diagnosis of Type 1 diabetes mellitus for at least 12 months
  3. Body Mass Index (BMI) ≤ 35 Kg/m2
  4. Basal insulin includes insulin Glargine or insulin Detemir
  5. Patient should be using bolus insulin defined as 2 to 4 doses of regular human insulin or rapid-acting analog at meals
  6. HbA1c ≥ 7.0% and ≤ 10.5%
  7. Fasting C-peptide ≤ 0.5 pmol/mL
  8. Willingness to adhere to protocol and perform all required tests
  9. Willing and able to review and sign the Informed Consent Form.
  10. If child bearing age, must use acceptable form of birth control (ligation, 2 forms of birth control)
  11. Willing to wear CGM devices and complete diaries.

Exclusion Criteria:

  1. Total daily insulin dose ≥ 1.5 IU/kg/day.
  2. History of recent blood transfusions (within previous 3 months), hemoglobinopathies, or any other conditions that effect HbA1c measurements
  3. Evidence of serious complications of diabetes (eg, Symptomatic autonomic neuropathy)
  4. Patients who are selected to but are unwilling or unable to participate in the MRI evaluation subset. (These patients may still participate in the non-MRI subset).
  5. Significant cardiovascular dysfunction or history within 12 months of Screening, eg, congestive heart failure (New York Heart Association Class III or IV), or clinically significant arrhythmia, myocardial infarction, cardiac surgery; history of valvular heart disease including mild or greater aortic insufficiency, or moderate or greater mitral insufficiency; recurrent syncope, transient ischemic attacks, or cerebrovascular accident
  6. Impaired liver function with elevated enzymes > 50% above the normal range at Screening. Patients with elevated liver enzymes may have the test repeated only at Visit 2 on a case-by-case basis at the request of the PI.
  7. Creatinine level > 2 mg/dL for men, and > 1.8 mg/dL for women at Screening.
  8. Patient on low carbohydrate diet, such as Atkins Diet
  9. History of Adrenal supplementation within 3 years of Screening.
  10. History of unawareness or SEVERE recurrent hypoglycemia, defined as a patient who is unaware of symptoms of hypoglycemia, or due to autonomic dysfunction, has no inherent warnings of hypoglycemia, and therefore requires outside assistance to rectify any episodes of hypoglycemia
  11. Patients treated with systemic corticosteroids (Sporadic use of inhaled, intraarticular, and topical corticosteroids is not considered systemic).
  12. Patients with triglyceride levels ≥500 mg/dL at Screening.
  13. Patients with a history of cancer within the past 5 years, excluding basal or squamous cell carcinoma localized to the skin.
  14. Epilepsy or other physical or medical conditions which could result in non-compliance with the study.
  15. Participation in a clinical trial or use of an investigational drug within 30 days prior to admission to this study
  16. Unwilling to discontinue use of an insulin pump for the duration of the study.
  17. Women who are pregnant, nursing, or planning to become pregnant during the course of the study.
  18. Patients on NPH as their basal insulin.
  19. Positive history of hepatitis A (within 12 months of Screening), or a positive history of hepatitis B, hepatitis C, or HIV at Screening.
  20. History of drug addiction and/or alcohol abuse within 12 months of Screening.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02794155
Other Study ID Numbers  ICMJE DP 01-2015-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Diasome Pharmaceuticals
Study Sponsor  ICMJE Diasome Pharmaceuticals
Collaborators  ICMJE Integrium
Investigators  ICMJE
Principal Investigator: David Klonoff, MD Mills-Peninsula Health Services
PRS Account Diasome Pharmaceuticals
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP