Evaluation of TTP399 in Patients With Type 1 Diabetes

• TTP399 (Drug): Phase 1: Participants will receive TTP399 administered orally up to 1200 mg taken once daily for 7 days
• TTP399 (Drug): Phase 2: Participants will receive TTP399 administered orally 800 mg taken once daily for 12 weeks
• Placebo Oral Tablet (Drug): Phase 2: Participants will receive Placebo oral tablets for 12 weeks

Primary outcomes

• Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 [Baseline (Day 1) to Week 13]: To evaluate the change in glycosylated hemoglobin (HbA1C) in Part 1 and Part 2 participants following multiple-day dosing (at 12 weeks) in subjects with T1MD. Sentinel participants were not evaluated for a change in HbA1C.
• Sentinel - Area Under the Concentration Time Curve (AUC) [Predose, 60, 90, 120, 150, 180, 240, 360 (6hr) and 540min (9hr) after dosing.]: AUC for Day 1 per dose level (400 mg, 800 mg, and 1200 mg) is AUC from 0 to 9 hours.
• Sentinel - Maximum Drug Concentration (Cmax) [Predose, 60, 90, 120, 150, 180, 240, 360 (6hr) and 540min (9hr) after dosing.]
• Sentinel - Time to Maximum Concentration (Tmax) [Predose, 60, 90, 120, 150, 180, 240, 360 (6hr) and 540min (9hr) after dosing.]

Secondary outcomes

• Percent Change From Baseline Time in Target Glycemic Range (70-180 mg/dL) [Baseline (Day 1) to Week 12]: To evaluate the change from baseline time in target range (24 hour)
• Percent Change From Baseline Time in Hypoglycemia (< 54 mg/dL) [Baseline (Day 1) to Week 12]: To evaluate the change from baseline time in hypoglycemia (< 54 mg/dL)
• Percent Change From Baseline Time in Hypoglycemia (< 70 mg/dL) [Baseline (Day 1) to Week 12]: To evaluate the change from baseline time in hypoglycemia (< 70 mg/dL)
• Percent Change From Baseline Time in Hyperglycemia (>180 mg/dL) [Baseline (Day 1) to Week 12]: To evaluate the change from baseline time in hypoglycemia (>180 mg/dL)
• Percent Change From Baseline Time in Hyperglycemia (>250 mg/dL) [Baseline (Day 1) to Week 12]: To evaluate the change from baseline time in hypoglycemia (>250 mg/dL)
• Percent Change From Baseline in Total Daily Insulin Use [Baseline (Day 1) to Week 12]: To evaluate the percent change from baseline in total daily insulin use at week 12.
• Change From Baseline in Bolus Insulin Use [Baseline (Day 1) to Week 12]: To evaluate the change from baseline in bolus insulin use
• Change From Baseline in Basal Insulin Use [Baseline (Day 1) to Week 12]: To evaluate the change from baseline in basal insulin use

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* People diagnosed with T1DM, confirmed diagnosis prior to 40 years of age and a diagnosed for minimum of 1 year.
* Type 1 diabetics using either continuous subcutaneous insulin infusion (with lispro or aspart) or multiple daily doses of insulin
* Willing to use adequate contraception
* No major surgeries or significant injuries within the past year and without an active infection.

Exclusion Criteria:

* Diagnosis of T2DM, severely uncontrolled T1DM, maturity-onset diabetes of the young, insulin-requiring T2DM, other unusual or rare forms of diabetes mellitus, diabetes resulting from a secondary disease
* Receipt of an investigational product within 30 days of the Screening Visit or any therapeutic protein or antibody within 90 days prior to Screening Visit or any previous treatment with TTP399.
* Living in the same household or related to another participant in this study.
* Two severe episodes of hypoglycemia that required assistance by a third party within 3 months of Screening Visit
* Use of antidiabetic medications other than insulin 3 months prior to Screening Visit, systemic corticosteroids 1 month prior to Screening Visit, weight loss medication 2 weeks prior to Screening Visit, and antipsychotic medications 3 months prior to Screening Visit.
* Participation in any formal weight loss program or contemplating such therapy during the trial.
* Recent history of use of non-prescribed controlled substances or illicit drugs.
* Current alcoholism or a history of excessive alcohol consumption within 2 years prior to screening
* History or presence of symptomatic autonomic neuropathy or chronic gastrointestinal disease.
* Personal history of long QT syndrome.
* Blood donation of approximately 1 pint (500 mL) within 8 weeks before Screening Visit
* History of hemolytic anemia or chronic transfusion requirement.
* History of cancer, other than non-melanoma skin cancer or uterine cervical cancer that required therapy in the past 5 years.
* Breastfeeding

Participant flow

Outcome results

• Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 (Primary), Least squares mean, percent change: Part 1 Placebo 0.08 +/- 0.2; Part 1 TTP399 800 mg -0.60 +/- 0.2; Part 2 Placebo 0.07 +/- 0.06; Part 2 TTP399 800 mg -0.14 +/- 0.06 (p <0.0001)
• Sentinel - Area Under the Concentration Time Curve (AUC) (Primary), Mean, ng*h/mL: Sentinel 400 mg 1778 +/- 992; Sentinel 800 mg 1482 +/- 341; Sentinel 1200 mg 4848 +/- 2663
• Sentinel - Maximum Drug Concentration (Cmax) (Primary), Mean, ng/mL: Sentinel 400 mg 645 +/- 219; Sentinel 800 mg 813 +/- 129; Sentinel 1200 mg 2038 +/- 1415
• Percent Change From Baseline Time in Target Glycemic Range (70-180 mg/dL) (Secondary), Mean, percent change: Part 1 Placebo -8 +/- 10; Part 1 TTP399 800 mg -3 +/- 8; Part 2 Placebo -7 +/- 14.0; Part 2 TTP399 800 mg 0.50 +/- 16
• Percent Change From Baseline Time in Hypoglycemia (< 54 mg/dL) (Secondary), Median, percent change: Part 1 Placebo -0.1 (-2 to 2); Part 1 TTP399 800 mg -0.1 (-3 to 0); Part 2 Placebo -0.5 (-8 to 8); Part 2 TTP399 800 mg -0.5 (-8 to 22)
• Percent Change From Baseline Time in Hypoglycemia (< 70 mg/dL) (Secondary), Mean, percent change: Part 1 Placebo -1 +/- 3; Part 1 TTP399 800 mg -1 +/- 3; Part 2 Placebo -2 +/- 5; Part 2 TTP399 800 mg -2 +/- 8
• Percent Change From Baseline Time in Hyperglycemia (>180 mg/dL) (Secondary), Mean, percent change: Part 1 Placebo 9 +/- 12; Part 1 TTP399 800 mg 5 +/- 8; Part 2 Placebo 10 +/- 17; Part 2 TTP399 800 mg 1 +/- 18
• Percent Change From Baseline Time in Hyperglycemia (>250 mg/dL) (Secondary), Mean, percent change: Part 2 Placebo 6 +/- 11; Part 2 TTP399 800 mg 2 +/- 12
• Percent Change From Baseline in Total Daily Insulin Use (Secondary), Mean, percent change: Part 1 Placebo -0.1 +/- 8.7; Part 1 TTP399 800 mg -1.7 +/- 14.7; Part 2 Placebo -1.6 +/- 16; Part 2 TTP399 800 mg -7.6 +/- 10.1
• Change From Baseline in Bolus Insulin Use (Secondary), Mean, units/kg/day: Part 1 Placebo -5.9 +/- 17.5; Part 1 TTP399 800 mg -1 +/- 31.8; Part 2 Placebo -3.9 +/- 28.4; Part 2 TTP399 800 mg -8.4 +/- 22.7
• Change From Baseline in Basal Insulin Use (Secondary), Mean, units/kg/day: Part 1 Placebo 4.4 +/- 7.7; Part 1 TTP399 800 mg -2.3 +/- 10.3; Part 2 Placebo -0.5 +/- 11.6; Part 2 TTP399 800 mg -5.4 +/- 7.1
• Sentinel - Time to Maximum Concentration (Tmax) (Primary), Median, hour: Sentinel 400 mg 1.5 (1.5 to 2.5); Sentinel 800 mg 1.5 (1.5 to 2.0); Sentinel 1200 mg 2.5 (1.5 to 3.0)

Adverse events

Time frame: Treatment-emergent adverse events were those reported at baseline up to 12 weeks (±3) days after the last dose. Unresolved AEs were followed up by the investigator for as long as medically indicated. Sentinel group reported at baseline up to 28 days after the last dose.

Serious adverse events by term

Other adverse events by term

• Results publication: Klein KR, Freeman JLR, Dunn I, Dvergsten C, Kirkman MS, Buse JB, Valcarce C; SimpliciT1 research group. The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes. Diabetes Care. 2021 Apr;44(4):960-968. doi: 10.2337/dc20-2684. Epub 2021 Feb 23. PMID 33622669

• Study Protocol (PDF, 2019-02-08)
• Statistical Analysis Plan (PDF, 2019-12-13)

• Carmen Valcarce, Ph.D., Study director, vTv Therapeutics, LLC