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A Comparison of Postprandial Glucose After a MMTT, and the Metabolic Effects of Insulin Withdrawal in a Crossover Study in Subjects With Type 1 Diabetes

Y

Youngene Therapeutics

Status and phase

Completed
Phase 2

Conditions

Diabetes Mellitus, Type 1
Diabetes
Diabetes Mellitus
Type1diabetes

Treatments

Drug: Dapagliflozin
Drug: YG1699

Study type

Interventional

Funder types

Industry

Identifiers

NCT04956263
YG1699-201

Details and patient eligibility

About

This is an inpatient treatment, double-blind, randomized, 3-way crossover study in T1DM subjects using insulin pump therapy.

Full description

Subjects will be randomized to one of 6 treatment sequences. The randomized study drug will be administered once daily for 7 days throughout each of 3 treatment periods. Each subject will attend an in-house baseline period, the NoTreatment period, and 3 in-house treatment periods, The Active Periods, where the same assessments will be performed. At each of the in-house periods, a MMTT will be carried out on the sixth day of dosing and an insulin withdrawal test will be carried out on the seventh day of dosing.

Postprandial glycemic excursion after a MMTT will be evaluated one day prior to an insulin withdrawal test. An insulin pumps with different modes (such as open loop/closed loop) the mode used at screening will be the mode used throughout the study. Unblinded continuous glucose monitoring (CGM) will be initiated at the start of the 7-day Baseline Period (Day -7) and discontinued at End of Treatment (Day 34).

Enrollment

19 patients

Sex

All

Ages

18 to 60 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

  1. Subjects ≥ 18 to ≤ 60 years of age at the time of signing the informed consent.
  2. Subjects diagnosed with T1DM for ≥ 12 months.
  3. Subjects who are currently using an approved insulin pump, with a stable basal insulin dose. Stable is defined as < 20% change of dose during the last 2 weeks prior to Screening.
  4. HbA1c < 9.5%.
  5. C-peptide after carbohydrate ingestion of < 0.3 nmol/L, with simultaneous plasma glucose > 90 mg/dL. (If necessary, subjects may consume carbohydrates to raise blood glucose over 90 mg/dL as measured by YSI prior to drawing blood for C-peptide. This may be repeated as needed to ensure C-peptide is assessed when plasma glucose concentration is > 90 mg/dL).
  6. Fasting BOHB ≤ 0.6 mmol/L.
  7. Body mass index (BMI) within the range ≥ 18.5 to ≤ 27.0 kg/m2.
  8. Female subjects must be non-pregnant and non-lactating.
  9. Females of childbearing potential must use highly effective contraceptive methods, stable at least 2 months prior to the screening. Male subjects must be surgically sterile, abstinent or if engaged in sexual relations of childbearing potential, the subject and his partner must be using acceptable methods of contraception.
  10. Capable of giving signed informed consent and willing to follow study procedures and commitment to the study duration

Exclusion criteria

  1. Subject has a diagnosis of type 2 diabetes (T2DM).

  2. Subject who has acute proliferative retinopathy or maculopathy, requiring acute treatment within 3 months of Screening.

  3. Subject who has ≥ 3 Level 2 or ≥ 1 Level 3 hypoglycemic events, or hypoglycemic unawareness, or had a severe hypoglycemic event (Level 3) within 1 month prior to Screening.

  4. Subject who has had DKA or nonketotic hyperosmolar state within 1 month of Screening, OR ≥ 2 events of DKA or nonketotic hyperosmolar state within 6 months of Screening.

  5. Subject with uncontrolled hypertension, defined as persistent blood pressure (BP) systolic or diastolic > 150/90 mmHg, or hypotension, defined as BP < 90/60 mmHg. (Subjects BP may be re-checked per site SOP)

  6. Subject with any clinically significant active disease of the gastrointestinal system (peptic ulcers, severe GERD, gastroparesis, any malabsorption/motility disorders, or chronic constipation). severe gastroparesis, and/or severe neuropathy, especially autonomic neuropathy, as judged by the Investigator.

  7. Subject with history of heart disease, defined as symptomatic heart failure (New York Heart Association class III or IV), myocardial infarction, coronary artery bypass graft surgery, or angioplasty, unstable angina requiring medication, transient ischemic attack, cerebral infarct, or cerebral hemorrhage.

  8. Subject with presence of clinically significant ECG findings (eg, QTcF > 450 msec for males, QTcF > 470 msec for females, left bundle branch block [LBBB],cardiac arrythmia) at Screening that, in the opinion of the Investigator, may interfere with any aspect of study conduct or interpretation of results, or may present a safety issue to that particular subject.

  9. Subject with history of renal disease or abnormal kidney function tests at Screening (eGFR < 60 mL/min/1.73m2 as estimated using the CKD-EPI Creatinine equation).

  10. History of hereditary glucose-galactose malabsorption or primary renal glucosuria

  11. Subjects with a thyroid disease, not adequately controlled. (Subjects with TSH outside of reference range due to incorrect treatment may be re-screened and included after successful treatment correction.)

  12. Subject with a history of significant liver disease, transaminases (AST, ALT) ≥ 2 x upper limit normal (ULN), or total bilirubin >1.5x ULN. (Laboratory results may be re-checked once on a separate day per Investigator discretion)

  13. Subject shows evidence of significant active neuropsychiatric disease, or chronic seizures, or major neurological disorders. Subjects that are stable and controlled by stable doses of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), antipsychotics and lithium for ≥ 3 months prior to screening may be allowed based on the judgement of the investigator.

  14. Subject with a history of neoplastic disease within the past 5 years, except for adequately treated non-melanomatous skin carcinoma or other malignancies which have been successfully treated ≥10 years prior to screening.

  15. Subject with a previous surgical treatment for obesity (bariatric surgery, gastric banding, etc.) or any other gastrointestinal surgery that may induce malabsorption, history of bowel resection > 20 cm, or any GI procedure for weight loss (including LAP-BAND®).

  16. Subject with history of any major surgery within 6 months.

  17. Subject with current use of any prescribed or non-prescribed drugs (other than the allowed current treatment for T1DM).

  18. Subject with a history of any serious adverse reaction or hypersensitivity to any of the investigational product components or medicinal products with similar chemical structure, a history of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food.

  19. Subject with a history or positive test of hepatitis B surface antigen (HBsAg), or positive test for Hepatitis C, or presence of human immunodeficiency virus type 1 (HIV-1) or 2 (HIV-2) antibodies.

  20. Subject with history of any active infection, including Coronavirus disease (COVID-19), other than mild viral illness within 30 days prior to the first dosing. (Subjects will follow site specific COVID-19 protocols during the entire study)

  21. Subjects with immunizations within 14 days prior to first dosing. Administration of coronavirus (Covid-19) vaccine within 5 days prior to first dosing or if scheduled during any in-house periods. Vaccination for COVID-19 is allowed during the study if a washout period of 5 days after vaccine administration is followed before any dosing.

  22. Subject with history of alcohol abuse as judged by the Investigator within approximately 1 year. Average daily alcohol intake > 2 drinks of alcoholic beverages for men and > 1 drinks of alcoholic beverages for women. (One drink is defined as 12 fluid ounces of beer (5% alcohol), 5 fluid ounces of wine (12% alcohol) or 1.5 fluid ounces of distilled spirits (40% alcohol).

    Positive alcohol breath test at Screening and check-in.

  23. Subjects with a history of smoking > 5 cigarettes per day or equivalent use of any tobacco product (e.g., nicotine patch) within 6 months prior to Screening. Subjects must be able to refrain from smoking during each in-house period.

  24. Subject with a history of illicit drug abuse, including marijuana, within approximately 3 months or evidence of current use as judged by the Investigator. Positive drug test, including marijuana, at Screening and check-in.

  25. Subject who participated in an investigational drug/device study within 30 days or 5 half-lives within the last dose of any study drug, whichever is longer.

  26. Subjects unwilling to use study-supplied CGM throughout the study duration or to abstain from using > 1000 mg acetaminophen every 6 hours, per CGM safety information, or is unable to tolerate adhesive tape or has any unresolved adverse skin reaction in the area of the sensor placement.

  27. Subject with donation or loss of > 500 mL of blood within 56 days.

  28. Subject who is unwilling to adhere to the protocol requirements during the study or unwilling to cooperate, or comply with the requirements of this study, or is considered by the Investigator to be an unsuitable candidate for the study.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Crossover Assignment

Masking

Quadruple Blind

19 participants in 3 patient groups

Treatment A
Experimental group
Description:
YG1699 10 mg
Treatment:
Drug: YG1699
Treatment B
Experimental group
Description:
YG1699 25 mg
Treatment:
Drug: YG1699
Treatment C
Active Comparator group
Description:
Dapagliflozin 10 mg
Treatment:
Drug: Dapagliflozin

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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