Diabetes Mellitus, Type 1
Conditions
Brief summary
The purpose of this study is to evaluate the safety and efficacy of TTP399 in Type 1 diabetics. This study will be in 2 phases: phase 1 will evaluate the safety of different TTP399 dosage regimens over 1 week of daily dosing. Phase 2 will evaluate the safety and efficacy of a TTP399 dosing regimen over 12 weeks of daily dosing.
Interventions
DRUGTTP399
Phase 1: Participants will receive TTP399 administered orally up to 1200 mg taken once daily for 7 days
DRUGPlacebo Oral Tablet
Phase 2: Participants will receive Placebo oral tablets for 12 weeks
Sponsors
Juvenile Diabetes Research Foundation
vTv Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) |
| Change From Baseline in Basal Insulin Use | Baseline (Day 1) to Week 12 | To evaluate the change from baseline in basal insulin use |
| Change From Baseline in Bolus Insulin Use | Baseline (Day 1) to Week 12 | To evaluate the change from baseline in bolus insulin use |
| 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) |
Countries
United States
Participant flow
Pre-assignment details
A total of 110 participants were randomized to the study groups: Sentinel, Part 1, and Part 2. Sentinel participants were the same participants throughout the dose levels.
Participants by arm
| Arm | Count |
|---|---|
| Sentinel Sentinel: Participants who received TTP399 400 mg, 800 mg, and 1200 mg administered orally once daily for 1 week per dose level. | 5 |
| Part 1 TTP399 800 mg TTP399 Part 1: Participants who received TTP399 800 mg administered orally once daily for 12 weeks with a 1-week follow-up after the last dose was administered. | 8 |
| Part 1 Placebo Placebo Part 1: Participants who received placebo tablets administered orally once daily for 12 weeks with a 1-week follow-up after the last dose was administered. | 11 |
| Part 2 TTP399 800 mg TTP399 Part 2: Participants who received TTP399 800 mg administered orally once daily for 12 weeks with a 1-week follow-up after the last dose was administered. | 40 |
| Part 2 Placebo Placebo Part 2: Participants who received placebo tablets administered orally once daily for 12 weeks with a 1-week follow-up after the last dose was administered. | 45 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Randomization Error | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Sentinel | Total | Part 2 Placebo | Part 2 TTP399 800 mg | Part 1 Placebo | Part 1 TTP399 800 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 32 years STANDARD_DEVIATION 7.4 | 42.5 years STANDARD_DEVIATION 13.76 | 42 years STANDARD_DEVIATION 13.26 | 43 years STANDARD_DEVIATION 15.26 | 47 years STANDARD_DEVIATION 10.1 | 38 years STANDARD_DEVIATION 15.71 |
| BMI | 24 kg/m2 STANDARD_DEVIATION 3 | 28 kg/m2 STANDARD_DEVIATION 3.8 | 28 kg/m2 STANDARD_DEVIATION 3.76 | 28 kg/m2 STANDARD_DEVIATION 4.16 | 29 kg/m2 STANDARD_DEVIATION 4.13 | 28 kg/m2 STANDARD_DEVIATION 3.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 106 Participants | 43 Participants | 39 Participants | 11 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Glycosylated hemoglobin (HbA1c) | 6.9 Percent HbA1c in blood STANDARD_DEVIATION 0.7 | 7.45 Percent HbA1c in blood STANDARD_DEVIATION 0.7 | 7.52 Percent HbA1c in blood STANDARD_DEVIATION 0.59 | 7.66 Percent HbA1c in blood STANDARD_DEVIATION 0.56 | 7.36 Percent HbA1c in blood STANDARD_DEVIATION 0.41 | 7.20 Percent HbA1c in blood STANDARD_DEVIATION 0.42 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 104 Participants | 43 Participants | 38 Participants | 11 Participants | 7 Participants |
| Sex: Female, Male Female | 3 Participants | 56 Participants | 25 Participants | 15 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 53 Participants | 20 Participants | 25 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 56 | 0 / 49 |
| other Total, other adverse events | 2 / 5 | 1 / 5 | 2 / 5 | 32 / 56 | 25 / 49 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 1 / 56 | 1 / 49 |
Outcome results
Primary
Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12
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.
Time frame: Baseline (Day 1) to Week 13
Population: Part 1 and Part 2 populations are the full analysis of randomized subjects. Sentinel participants were not evaluated for a change in HbA1C.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 | 0.08 percent change | Standard Error 0.2 |
| Part 1 TTP399 800 mg | Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 | -0.60 percent change | Standard Error 0.2 |
| Part 2 Placebo | Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 | 0.07 percent change | Standard Error 0.06 |
| Part 2 TTP399 800 mg | Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 12 | -0.14 percent change | Standard Error 0.06 |
p-value: <0.000195% CI: [-0.39, -0.04]ANCOVA
Primary
Sentinel - Area Under the Concentration Time Curve (AUC)
AUC for Day 1 per dose level (400 mg, 800 mg, and 1200 mg) is AUC from 0 to 9 hours.
Time frame: Predose, 60, 90, 120, 150, 180, 240, 360 (6hr) and 540min (9hr) after dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Sentinel - Area Under the Concentration Time Curve (AUC) | 1778 ng*h/mL | Standard Deviation 992 |
| Part 1 TTP399 800 mg | Sentinel - Area Under the Concentration Time Curve (AUC) | 1482 ng*h/mL | Standard Deviation 341 |
| Part 2 Placebo | Sentinel - Area Under the Concentration Time Curve (AUC) | 4848 ng*h/mL | Standard Deviation 2663 |
Primary
Sentinel - Maximum Drug Concentration (Cmax)
Time frame: Predose, 60, 90, 120, 150, 180, 240, 360 (6hr) and 540min (9hr) after dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Sentinel - Maximum Drug Concentration (Cmax) | 645 ng/mL | Standard Deviation 219 |
| Part 1 TTP399 800 mg | Sentinel - Maximum Drug Concentration (Cmax) | 813 ng/mL | Standard Deviation 129 |
| Part 2 Placebo | Sentinel - Maximum Drug Concentration (Cmax) | 2038 ng/mL | Standard Deviation 1415 |
Primary
Sentinel - Time to Maximum Concentration (Tmax)
Time frame: Predose, 60, 90, 120, 150, 180, 240, 360 (6hr) and 540min (9hr) after dosing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Placebo | Sentinel - Time to Maximum Concentration (Tmax) | 1.5 hour |
| Part 1 TTP399 800 mg | Sentinel - Time to Maximum Concentration (Tmax) | 1.5 hour |
| Part 2 Placebo | Sentinel - Time to Maximum Concentration (Tmax) | 2.5 hour |
Secondary
Change From Baseline in Basal Insulin Use
To evaluate the change from baseline in basal insulin use
Time frame: Baseline (Day 1) to Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Change From Baseline in Basal Insulin Use | 4.4 units/kg/day | Standard Deviation 7.7 |
| Part 1 TTP399 800 mg | Change From Baseline in Basal Insulin Use | -2.3 units/kg/day | Standard Deviation 10.3 |
| Part 2 Placebo | Change From Baseline in Basal Insulin Use | -0.5 units/kg/day | Standard Deviation 11.6 |
| Part 2 TTP399 800 mg | Change From Baseline in Basal Insulin Use | -5.4 units/kg/day | Standard Deviation 7.1 |
Secondary
Change From Baseline in Bolus Insulin Use
To evaluate the change from baseline in bolus insulin use
Time frame: Baseline (Day 1) to Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Change From Baseline in Bolus Insulin Use | -5.9 units/kg/day | Standard Deviation 17.5 |
| Part 1 TTP399 800 mg | Change From Baseline in Bolus Insulin Use | -1 units/kg/day | Standard Deviation 31.8 |
| Part 2 Placebo | Change From Baseline in Bolus Insulin Use | -3.9 units/kg/day | Standard Deviation 28.4 |
| Part 2 TTP399 800 mg | Change From Baseline in Bolus Insulin Use | -8.4 units/kg/day | Standard Deviation 22.7 |
Secondary
Percent Change From Baseline in Total Daily Insulin Use
To evaluate the percent change from baseline in total daily insulin use at week 12.
Time frame: Baseline (Day 1) to Week 12
Population: Part 1 is the full analysis set. Part 2 is all randomized subjects who received at least 1 dose of the investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Percent Change From Baseline in Total Daily Insulin Use | -0.1 percent change | Standard Deviation 8.7 |
| Part 1 TTP399 800 mg | Percent Change From Baseline in Total Daily Insulin Use | -1.7 percent change | Standard Deviation 14.7 |
| Part 2 Placebo | Percent Change From Baseline in Total Daily Insulin Use | -1.6 percent change | Standard Deviation 16 |
| Part 2 TTP399 800 mg | Percent Change From Baseline in Total Daily Insulin Use | -7.6 percent change | Standard Deviation 10.1 |
Secondary
Percent Change From Baseline Time in Hyperglycemia (>180 mg/dL)
To evaluate the change from baseline time in hypoglycemia (\>180 mg/dL)
Time frame: Baseline (Day 1) to Week 12
Population: Part 1 is the full analysis set. Part 2 is all randomized subjects who received at least 1 dose of the investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Percent Change From Baseline Time in Hyperglycemia (>180 mg/dL) | 9 percent change | Standard Deviation 12 |
| Part 1 TTP399 800 mg | Percent Change From Baseline Time in Hyperglycemia (>180 mg/dL) | 5 percent change | Standard Deviation 8 |
| Part 2 Placebo | Percent Change From Baseline Time in Hyperglycemia (>180 mg/dL) | 10 percent change | Standard Deviation 17 |
| Part 2 TTP399 800 mg | Percent Change From Baseline Time in Hyperglycemia (>180 mg/dL) | 1 percent change | Standard Deviation 18 |
Secondary
Percent Change From Baseline Time in Hyperglycemia (>250 mg/dL)
To evaluate the change from baseline time in hypoglycemia (\>250 mg/dL)
Time frame: Baseline (Day 1) to Week 12
Population: Time in hypoglycemia \>250mg/dL was only evaluated in Part 2 of the study. Part 2 is all randomized subjects who received at least 1 dose of the investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Percent Change From Baseline Time in Hyperglycemia (>250 mg/dL) | 6 percent change | Standard Deviation 11 |
| Part 1 TTP399 800 mg | Percent Change From Baseline Time in Hyperglycemia (>250 mg/dL) | 2 percent change | Standard Deviation 12 |
Secondary
Percent Change From Baseline Time in Hypoglycemia (< 54 mg/dL)
To evaluate the change from baseline time in hypoglycemia (\< 54 mg/dL)
Time frame: Baseline (Day 1) to Week 12
Population: Part 1 is the full analysis set. Part 2 is all randomized subjects who received at least 1 dose of the investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Placebo | Percent Change From Baseline Time in Hypoglycemia (< 54 mg/dL) | -0.1 percent change |
| Part 1 TTP399 800 mg | Percent Change From Baseline Time in Hypoglycemia (< 54 mg/dL) | -0.1 percent change |
| Part 2 Placebo | Percent Change From Baseline Time in Hypoglycemia (< 54 mg/dL) | -0.5 percent change |
| Part 2 TTP399 800 mg | Percent Change From Baseline Time in Hypoglycemia (< 54 mg/dL) | -0.5 percent change |
Secondary
Percent Change From Baseline Time in Hypoglycemia (< 70 mg/dL)
To evaluate the change from baseline time in hypoglycemia (\< 70 mg/dL)
Time frame: Baseline (Day 1) to Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Percent Change From Baseline Time in Hypoglycemia (< 70 mg/dL) | -1 percent change | Standard Deviation 3 |
| Part 1 TTP399 800 mg | Percent Change From Baseline Time in Hypoglycemia (< 70 mg/dL) | -1 percent change | Standard Deviation 3 |
| Part 2 Placebo | Percent Change From Baseline Time in Hypoglycemia (< 70 mg/dL) | -2 percent change | Standard Deviation 5 |
| Part 2 TTP399 800 mg | Percent Change From Baseline Time in Hypoglycemia (< 70 mg/dL) | -2 percent change | Standard Deviation 8 |
Secondary
Percent Change From Baseline Time in Target Glycemic Range (70-180 mg/dL)
To evaluate the change from baseline time in target range (24 hour)
Time frame: Baseline (Day 1) to Week 12
Population: Part 1 is the full analysis set. Part 2 is all randomized subjects who received at least 1 dose of the investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Placebo | Percent Change From Baseline Time in Target Glycemic Range (70-180 mg/dL) | -8 percent change | Standard Deviation 10 |
| Part 1 TTP399 800 mg | Percent Change From Baseline Time in Target Glycemic Range (70-180 mg/dL) | -3 percent change | Standard Deviation 8 |
| Part 2 Placebo | Percent Change From Baseline Time in Target Glycemic Range (70-180 mg/dL) | -7 percent change | Standard Deviation 14 |
| Part 2 TTP399 800 mg | Percent Change From Baseline Time in Target Glycemic Range (70-180 mg/dL) | 0.50 percent change | Standard Deviation 16 |