Healthy
Conditions
Brief summary
This is a Phase 1, open-label, fixed-sequence, 3-period study to evaluate the effect of multiple doses of itraconazole and a single dose of cyclosporine on the single-dose PK of PF-07081532 in otherwise healthy, overweight or obese, adult female and male participants. The 3 study periods will be conducted consecutively without a break.
Interventions
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Otherwise healthy female and male participants must be at least 18 years of age at the time of signing the ICD (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, physical examination, including blood pressure and pulse rate measurement, standard 12-lead ECG and clinical laboratory tests). 2. BMI: ≥25.0 kg/m2 at Screening. 3. Stable body weight, defined as \<5 kg change (per participant report) for 90 days before Screening.
Exclusion criteria
1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). 2. Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at Screening. 3. Any malignancy not considered cured (except basal cell carcinoma and squamous cell carcinoma of the skin) 4. Personal or family history of MTC or MEN2, or study participants with suspected MTC per the investigator's judgment. 5. Acute pancreatitis, a history of repeated episodes of acute pancreatitis, or history of chronic pancreatitis. 6. Symptomatic gallbladder disease. 7. Medical history or characteristics suggestive of genetic or syndromic obesity or obesity induced by other endocrinological disorders (eg, Cushing Syndrome). 8. History of depressive disorder or history of other severe psychiatric disorders (eg, schizophrenia or bipolar disorder) within the last 2 years from screening. 9. Known medical history of active liver disease, including chronic hepatitis B or C, primary biliary cirrhosis, alcoholic liver disease, primary sclerosing cholangitis, autoimmune hepatitis, overlap syndrome, or prior known drug-induced liver injury. 10. History of HIV infection. 11. Any lifetime history of a suicide attempt. 12. Use of prohibited medications 13. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. 14. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that mayaffect participant safety or interpretation of study result. 15. Participants with clinical laboratory test abnormalities at Screening. -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3. | AUCinf is area under the plasma concentration-time profile from time zero extrapolated to infinite time. AUCinf is caluculated by AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Laboratory Abnormalities | Baseline (pre-dose on Day 1), Period 2 Day 5 (Study Day 10), and Period 3 Day 10 (Study Day 20) | Participants with laboratory abnormalities (without regard to baseline abnormality) that met pre-specified criteria: For HEMATOLOGY, 1) Erythrocyte (Ery.) Mean Corpuscular Volume (fL) \< 0.9\*Lower limit of normal (LLN), 2) Ery. Mean Corpuscular Hemoglobin (picograms \[pg\]/cell) \< 0.9\*LLN; 3） Eosinophils/Leukocytes (%)\> 1.2\*upper limit of normal (ULN); for CLINICAL CHEMISTRY, Urate (mg/dL)\> 1.2\*ULN; for URINALYSIS, Urine Hemoglobin (Scalar)≥ 1. |
| Number of Participants Meeting Pre-Specified Criteria of Vital Signs | Pre-dose Day 1 in periods 1, 2 and 3 (Study Days 1, 6, and 11, respectively), and prior to discharge on Period 3 Day 10 (Study Day 20) | Pre-specified criteria of vital signs included: Supine diastolic blood pressure (BP) \<50mmHg, change from baseline maximum (max) decrease or increase \>=20mmHg; supine pulse rate min\< 40 beats per minute (bpm), max\> 120 bpm; Supine systolic BP: Value \<90 mmHg, change from baseline max decrease or increase \>=30mmHg |
| Change From Baseline in Body Weight at the End of Periods 1, 2, and 3 | Baseline (pre-dose on Day 1), Day 5 of Period 1 (Study Day 5), Day 5 of Period 2 (Study Day 10), and Day 10 of Period 3 (Study Day 20) | Observed value at baseline and change from baseline in body weight at Day 5 of Period 1 , Day 5 of Period 2, and Day 10 of Period 3 were summarized. |
| Number of Participants Meeting Pre-Specified Criteria of Electrocardiogram (ECGs) | Pre-dose Day 1 in periods 1, 2 and 3 (Study Days 1, 6, and 11, respectively), and prior to discharge on Period 3 Day 10 (Study Day 20) | The pre-specified criteria of ECG included: QT interval, aggregated: value \>500 millisecond (msec); corrected QT Fridericia method (QTCF) interval, aggregated: 450\<=value\<480 msec, 480\<=value\<500 msec, value\>=500 msec, 30\<=changes\<60msec, and changes\>=60msec. |
| Number of Participants With Suicidal Ideation or Behavior According to Columbia Suicide Severity Rating Scale (C-SSRS) | Period 1 Day -1 (Study Day -1), Period 3 Day 10 (Study Day 20) or Early Termination visit | The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Participants who respond yes to any question related to suicidal ideation or behavioral are reported in this outcome measure. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From the first dose up to 35 days after administration of the final dose of study intervention (Period 3 Day 9, Study Day 19), the maximum duration was 54 Days | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Any AEs occurring following start of treatment were considered as treatment emergent adverse event (TEAE). Events that occur during follow-up within the lag time of up to 35 days after the last dose of study intervention were counted as treatment emergent and attributed to the last treatment taken. |
| Maximum Observed Plasma Concentration (Cmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3. | Cmax is the maximum observed concentration and is observed directly from data. |
| Time to Cmax (Tmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3. | Tmax is the Time to Cmax and is observed directly from data as time of first occurrence. |
| Apparent Oral Clearance (CL/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3. | CL/F is the apparent oral clearance and is calculated by Dose/AUCinf. |
| Apparent Oral Volume of Distribution (Vz/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3. | Vz/F is the apparent volume of distribution and is calculated by Dose/ (AUCinf\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve |
| Terminal Half-life (t1/2) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3. | T1/2 is calculated by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. |
| Number of Participants With a Score of ≥15 on Patient Health Questionnaire-9 (PHQ-9) | Period 1 Day -1 (Study Day -1), Period 3 Day 10 (Study Day 20) or Early Termination visit | PHQ9-9 is a 9 item self-report scale for the assessment of depressive symptoms. A PHQ-9 score of ≥15 indicates clinically significant depression and was reported in this outcome measure. The total score ranges from 0 to 27 with the following interpretation: Score 1-4: minimal depression; Score 5-9: Mild depression; Score 10-14: moderate depression; Score 15-19 moderately severe depression; Score 20-27: Severe depression |
Countries
United States
Participant flow
Pre-assignment details
A total of 16 participants were enrolled in the study. All enrolled participants received 3-period treatments in a fixed sequence. All enrolled participants were treated and completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Lotiglipron Then Lotiglipron + Cyclosporine Then Lotiglipron + Itraconazole Period 1 (Study Days -1 to 5): Participants received 40 mg SD lotiglipron orally on Day 1 of Period 1. Period 1 was followed by Period 2.
Period 2 (Study Days 6 to 10): Participants received 40 mg SD lotiglipron orally and a 600 mg SD cyclosporine orally on Day 1 of Period 2. Period 2 was followed by Period 3.
Period 3 (Study Days 11 to 20): Participants received 200 mg SD itraconazole orally for 9 days and 40 mg SD lotiglipron orally on Day 4 of Period 3.
Participants were followed up to maximum of 35 days from the last dose of study intervention. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Lotiglipron Then Lotiglipron + Cyclosporine Then Lotiglipron + Itraconazole |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 36.2 Years STANDARD_DEVIATION 11.54 |
| Body Mass Index (BMI) | 28.6 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 11 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine
AUCinf is area under the plasma concentration-time profile from time zero extrapolated to infinite time. AUCinf is caluculated by AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.
Time frame: Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Population: All participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported. The outcome measure was reported by 3 arms to characterize the effect of MD itraconazole and SD cyclosporine on the single dose PK of lotiglipron.~The 120-hour PK samples collected in Period 1 was the same as the pre-dose PK samples in Periods 2. The 120-hour PK sample from Period 2 was taken on Day 1 of Period 3 prior to itraconazole dose administration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 81800 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 49 |
| Experimental: Period 2: Lotiglipron + Cyclosporine | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 162800 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 62 |
| Experimental: Period 3: Itraconazole+Lotiglipron | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 212900 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 36 |
Comparison: Natural loge transformed Cmax of PF-07081532 administered without cyclosporine (Reference) or coadministered with cyclosporine (Test) were analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test/Reference) and corresponding 90% CIs was obtained from the models. The ratios (and 90% CIs) were expressed as percentages.90% CI: [162.13, 236.71]
Comparison: Natural loge transformed Cmax of PF-07081532 administered without itraconazole (Reference) or coadministered with itraconazole (Test) were analyzed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test/Reference) and corresponding 90% CIs was obtained from the models. The ratios (and 90% CIs) were expressed as percentages.90% CI: [258.81, 307.55]
Secondary
Apparent Oral Clearance (CL/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine
CL/F is the apparent oral clearance and is calculated by Dose/AUCinf.
Time frame: Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Population: All participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported. The outcome measure was reported by 3 arms to characterize the effect of MD itraconazole and SD cyclosporine on the single dose PK of lotiglipron.~The 120-hour PK samples collected in Period 1 was the same as the pre-dose PK samples in Periods 2. The 120-hour PK sample from Period 2 was taken on Day 1 of Period 3 prior to itraconazole dose administration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Apparent Oral Clearance (CL/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 0.4890 Litre (L)/hr | Geometric Coefficient of Variation 49 |
| Experimental: Period 2: Lotiglipron + Cyclosporine | Apparent Oral Clearance (CL/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 0.2458 Litre (L)/hr | Geometric Coefficient of Variation 62 |
| Experimental: Period 3: Itraconazole+Lotiglipron | Apparent Oral Clearance (CL/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 0.1879 Litre (L)/hr | Geometric Coefficient of Variation 36 |
Secondary
Apparent Oral Volume of Distribution (Vz/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine
Vz/F is the apparent volume of distribution and is calculated by Dose/ (AUCinf\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve
Time frame: Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Population: All participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported. The outcome measure was reported by 3 arms to characterize the effect of MD itraconazole and SD cyclosporine on the single dose PK of lotiglipron.~The 120-hour PK samples collected in Period 1 was the same as the pre-dose PK samples in Periods 2. The 120-hour PK sample from Period 2 was taken on Day 1 of Period 3 prior to itraconazole dose administration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Apparent Oral Volume of Distribution (Vz/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 15.01 Litre | Geometric Coefficient of Variation 31 |
| Experimental: Period 2: Lotiglipron + Cyclosporine | Apparent Oral Volume of Distribution (Vz/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 8.261 Litre | Geometric Coefficient of Variation 47 |
| Experimental: Period 3: Itraconazole+Lotiglipron | Apparent Oral Volume of Distribution (Vz/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 11.91 Litre | Geometric Coefficient of Variation 28 |
Secondary
Change From Baseline in Body Weight at the End of Periods 1, 2, and 3
Observed value at baseline and change from baseline in body weight at Day 5 of Period 1 , Day 5 of Period 2, and Day 10 of Period 3 were summarized.
Time frame: Baseline (pre-dose on Day 1), Day 5 of Period 1 (Study Day 5), Day 5 of Period 2 (Study Day 10), and Day 10 of Period 3 (Study Day 20)
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Change From Baseline in Body Weight at the End of Periods 1, 2, and 3 | Baseline | 87.631 Kilogram (kg) | Standard Deviation 12.935 |
| Active Comparator: Period 1: Lotiglipron | Change From Baseline in Body Weight at the End of Periods 1, 2, and 3 | Day 5 of Period 1 | -1.631 Kilogram (kg) | Standard Deviation 1.1904 |
| Active Comparator: Period 1: Lotiglipron | Change From Baseline in Body Weight at the End of Periods 1, 2, and 3 | Day 5 of Period 2 | -1.956 Kilogram (kg) | Standard Deviation 1.4778 |
| Active Comparator: Period 1: Lotiglipron | Change From Baseline in Body Weight at the End of Periods 1, 2, and 3 | Day 10 of Period 3 | -2.256 Kilogram (kg) | Standard Deviation 1.6541 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine
Cmax is the maximum observed concentration and is observed directly from data.
Time frame: Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Population: All participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported. The outcome measure was reported by 3 arms to characterize the effect of MD itraconazole and SD cyclosporine on the single dose PK of lotiglipron.~The 120-hour PK samples collected in Period 1 was the same as the pre-dose PK samples in Periods 2. The 120-hour PK sample from Period 2 was taken on Day 1 of Period 3 prior to itraconazole dose administration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Maximum Observed Plasma Concentration (Cmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 4165 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 28 |
| Experimental: Period 2: Lotiglipron + Cyclosporine | Maximum Observed Plasma Concentration (Cmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 5207 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 35 |
| Experimental: Period 3: Itraconazole+Lotiglipron | Maximum Observed Plasma Concentration (Cmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 5180 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 24 |
Secondary
Number of Participants Meeting Pre-Specified Criteria of Electrocardiogram (ECGs)
The pre-specified criteria of ECG included: QT interval, aggregated: value \>500 millisecond (msec); corrected QT Fridericia method (QTCF) interval, aggregated: 450\<=value\<480 msec, 480\<=value\<500 msec, value\>=500 msec, 30\<=changes\<60msec, and changes\>=60msec.
Time frame: Pre-dose Day 1 in periods 1, 2 and 3 (Study Days 1, 6, and 11, respectively), and prior to discharge on Period 3 Day 10 (Study Day 20)
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Number of Participants Meeting Pre-Specified Criteria of Electrocardiogram (ECGs) | 0 Participants |
Secondary
Number of Participants Meeting Pre-Specified Criteria of Vital Signs
Pre-specified criteria of vital signs included: Supine diastolic blood pressure (BP) \<50mmHg, change from baseline maximum (max) decrease or increase \>=20mmHg; supine pulse rate min\< 40 beats per minute (bpm), max\> 120 bpm; Supine systolic BP: Value \<90 mmHg, change from baseline max decrease or increase \>=30mmHg
Time frame: Pre-dose Day 1 in periods 1, 2 and 3 (Study Days 1, 6, and 11, respectively), and prior to discharge on Period 3 Day 10 (Study Day 20)
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Number of Participants Meeting Pre-Specified Criteria of Vital Signs | 0 Participants |
Secondary
Number of Participants With a Score of ≥15 on Patient Health Questionnaire-9 (PHQ-9)
PHQ9-9 is a 9 item self-report scale for the assessment of depressive symptoms. A PHQ-9 score of ≥15 indicates clinically significant depression and was reported in this outcome measure. The total score ranges from 0 to 27 with the following interpretation: Score 1-4: minimal depression; Score 5-9: Mild depression; Score 10-14: moderate depression; Score 15-19 moderately severe depression; Score 20-27: Severe depression
Time frame: Period 1 Day -1 (Study Day -1), Period 3 Day 10 (Study Day 20) or Early Termination visit
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Number of Participants With a Score of ≥15 on Patient Health Questionnaire-9 (PHQ-9) | 0 Participants |
Secondary
Number of Participants With Laboratory Abnormalities
Participants with laboratory abnormalities (without regard to baseline abnormality) that met pre-specified criteria: For HEMATOLOGY, 1) Erythrocyte (Ery.) Mean Corpuscular Volume (fL) \< 0.9\*Lower limit of normal (LLN), 2) Ery. Mean Corpuscular Hemoglobin (picograms \[pg\]/cell) \< 0.9\*LLN; 3） Eosinophils/Leukocytes (%)\> 1.2\*upper limit of normal (ULN); for CLINICAL CHEMISTRY, Urate (mg/dL)\> 1.2\*ULN; for URINALYSIS, Urine Hemoglobin (Scalar)≥ 1.
Time frame: Baseline (pre-dose on Day 1), Period 2 Day 5 (Study Day 10), and Period 3 Day 10 (Study Day 20)
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Laboratory Abnormalities | HEMATOLOGY- Ery. Mean Corpuscular Volume (fL) < 0.9*LLN | 1 Participants |
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Laboratory Abnormalities | HEMATOLOGY-Ery. Mean Corpuscular Hemoglobin (pg/cell) < 0.9*LLN | 1 Participants |
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Laboratory Abnormalities | HEMATOLOGY-Eosinophils/Leukocytes (%)> 1.2*ULN | 1 Participants |
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Laboratory Abnormalities | CLINICAL CHEMISTRY-Urate (mg/dL)> 1.2*ULN | 1 Participants |
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Laboratory Abnormalities | URINALYSIS-URINE Hemoglobin (Scalar)≥ 1 | 1 Participants |
Secondary
Number of Participants With Suicidal Ideation or Behavior According to Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Participants who respond yes to any question related to suicidal ideation or behavioral are reported in this outcome measure.
Time frame: Period 1 Day -1 (Study Day -1), Period 3 Day 10 (Study Day 20) or Early Termination visit
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Suicidal Ideation or Behavior According to Columbia Suicide Severity Rating Scale (C-SSRS) | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Any AEs occurring following start of treatment were considered as treatment emergent adverse event (TEAE). Events that occur during follow-up within the lag time of up to 35 days after the last dose of study intervention were counted as treatment emergent and attributed to the last treatment taken.
Time frame: From the first dose up to 35 days after administration of the final dose of study intervention (Period 3 Day 9, Study Day 19), the maximum duration was 54 Days
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All causality TEAEs | 11 Participants |
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-Related TEAEs | 11 Participants |
| Active Comparator: Period 1: Lotiglipron | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All causality Treatment-emergent SAEs | 0 Participants |
Secondary
Terminal Half-life (t1/2) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine
T1/2 is calculated by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Time frame: Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Population: All participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported. The outcome measure was reported by 3 arms to characterize the effect of MD itraconazole and SD cyclosporine on the single dose PK of lotiglipron.~The 120-hour PK samples collected in Period 1 was the same as the pre-dose PK samples in Periods 2. The 120-hour PK sample from Period 2 was taken on Day 1 of Period 3 prior to itraconazole dose administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Terminal Half-life (t1/2) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 21.96 hr | Standard Deviation 6.1239 |
| Experimental: Period 2: Lotiglipron + Cyclosporine | Terminal Half-life (t1/2) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 24.14 hr | Standard Deviation 7.3865 |
| Experimental: Period 3: Itraconazole+Lotiglipron | Terminal Half-life (t1/2) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 45.02 hr | Standard Deviation 9.7607 |
Secondary
Time to Cmax (Tmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine
Tmax is the Time to Cmax and is observed directly from data as time of first occurrence.
Time frame: Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Population: All participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported. The outcome measure was reported by 3 arms to characterize the effect of MD itraconazole and SD cyclosporine on the single dose PK of lotiglipron.~The 120-hour PK samples collected in Period 1 was the same as the pre-dose PK samples in Periods 2. The 120-hour PK sample from Period 2 was taken on Day 1 of Period 3 prior to itraconazole dose administration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Comparator: Period 1: Lotiglipron | Time to Cmax (Tmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 6.00 hr |
| Experimental: Period 2: Lotiglipron + Cyclosporine | Time to Cmax (Tmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 6.00 hr |
| Experimental: Period 3: Itraconazole+Lotiglipron | Time to Cmax (Tmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine | 5.03 hr |