Non-alcoholic Fatty Liver Disease
Conditions
Brief summary
IN THIS PHASE 2A, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, 3 ARM, PARALLEL- GROUP STUDY, SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF PF-06835919 ADMINISTERED ONCE DAILY FOR 6 WEEKS WILL BE ASSESSED IN ADULTS WITH NONALCOHOLIC FATTY LIVER DISEASE
Interventions
DRUGPlacebo
0 mg
DRUGPF-06835919 Low Dose
75 mg once daily
DRUGPF-06835919 High Dose
300 mg once daily
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* BMI at least 28 kg/m2 * Type 2 diabetes and/or metabolic syndrome
Exclusion criteria
* Liver disease * Type 1 diabetes * Recent heart attack or stroke * Inability to have an MRI scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Whole Liver Fat at Week 6 | Baseline and Week 6 | The percent change from baseline in whole liver fat at Week 6 was assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF). MRI-PDFF generates measures of the fraction of mobile protons in the liver attributable to fat content and provides whole liver coverage so that fat content can be assessed across 8 Couinaud liver segments. Whole liver PDFF was calculated as follows: Whole Liver PDFF= PDFFs for (Segment I+Segment II+Segment III+Segment IVa+Segment IVb+Segment V+Segment VI+Segment+VII+Segment VIII) / (number of segments assessed). The same segments were to be used at both baseline and post-baseline time points in the calculation of whole liver PDFF to derive the percent change from baseline. The values of whole liver PDFF ranges from 0 to 100 and higher values represent higher liver fat. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Baseline up to Day 77 (28-35 days post last dose) | All-causality adverse events (AEs) were any untoward medical occurrence in a study participant who administered a product or medical device, the event need not necessarily have a causal relationship with the treatment or usage. Treatment-related AEs were any untoward medical occurrence in a study participant who administered a product or medical device, the event needed to have a causal relationship with the treatment or usage. A TEAE was defined as any event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments. |
| Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Baseline up to Day 56 (Week 8) | The vital sign categorical criteria included: Sitting DBP (diastolic blood pressure) millimeter of mercury (mmHg) Change \>= 20 mmHg increase Sitting SBP (systolic blood pressure) (mmHg) Change \>= 30 mmHg increase Sitting DBP (mmHg) Change \>= 20 mmHg decrease Sitting SBP (mmHg) Change \>= 30 mmHg decrease Sitting DBP (mmHg) Value \< 50 mmHg Sitting Pulse Rate (bpm) Value \< 40 bpm or Value \> 120 bpm Sitting SBP (mmHg) Value \< 90 mmHg |
| Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | Baseline up to Day 56 (Week 8) | The ECG categorical criteria included: PR Interval (msec) percent (%)Change \>= 25% increase when baseline \>200 or \>=50% increase when baseline \<=200 QRS Interval (msec) %Change \>= 50% increase QTcF Interval (Fridericia's Correction) (msec) increase 30 \<= Change \< 60 or Change \>= 60 PR Interval (msec) Value \>= 300 QRS Interval (msec) Value \>= 140 QTcF Interval (Fridericia's Correction) (msec) 450 \<= Value \<480 or 480 \<=Value \<500 or Value \>= 500 |
| Number of Participants With Laboratory Abnormalities | Baseline up to Day 56 (Week 8) | Below parameters were evaluated for laboratory tests: Hemoglobin, Hematocrit, Erythrocytes, Ery. Mean Copuscular Volume, Ery. Mean Copuscular Hemoglobin, Ery. Mean Corpuscular HGB Concentration, Platelets, Leukocytes, Lymphocytes, Neuprophils, Basophils, Eosinophils, Monocytes, Bilirubin, Direct Biliirubin, Indirect Bilirubin, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase, Alkaline Phosphatase, Protein, Albumin, Albumin, Blood Urea Nitrogen, Creatinine, Urate, Sodium, Potassium, Chloride, Calcium, Bicarbonate, Glucose-Fasting, pH, Urine Glucose, Ketone, Urine Protein, Urine Hemoglobin, Urobilinogen, Urine Bilirubin, Nitrite, Leukocyte Esterase, Urine Erythocytes, Urine leukocytes, Hyaline Casts, Urine Creatinine. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to PF-06835919 tablets once daily (QD) were administered orally. | 19 |
| PF-06835919 75 mg PF-06835919 75 mg tablets QD were administered orally. | 17 |
| PF-06835919 300 mg PF-06835919 300 mg tablets QD were administered orally. | 17 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | PF-06835919 75 mg | PF-06835919 300 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 51.00 Years STANDARD_DEVIATION 9.67 | 52.82 Years STANDARD_DEVIATION 8.17 | 52.29 Years STANDARD_DEVIATION 9.26 | 52.00 Years STANDARD_DEVIATION 8.94 |
| Age, Customized 18-44 Years | 6 Participants | 2 Participants | 3 Participants | 11 Participants |
| Age, Customized 45-64 Years | 13 Participants | 15 Participants | 14 Participants | 42 Participants |
| Age Range | 53.00 Years | 54.00 Years | 54.00 Years | 54.00 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 6 Participants | 10 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 11 Participants | 7 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 6 Participants | 5 Participants | 13 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 17 Participants | 10 Participants | 12 Participants | 39 Participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 10 Participants | 26 Participants |
| Sex: Female, Male Male | 12 Participants | 8 Participants | 7 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 5 / 19 | 4 / 17 | 5 / 17 |
| serious Total, serious adverse events | 0 / 19 | 0 / 17 | 0 / 17 |
Outcome results
Primary
Percent Change From Baseline in Whole Liver Fat at Week 6
The percent change from baseline in whole liver fat at Week 6 was assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF). MRI-PDFF generates measures of the fraction of mobile protons in the liver attributable to fat content and provides whole liver coverage so that fat content can be assessed across 8 Couinaud liver segments. Whole liver PDFF was calculated as follows: Whole Liver PDFF= PDFFs for (Segment I+Segment II+Segment III+Segment IVa+Segment IVb+Segment V+Segment VI+Segment+VII+Segment VIII) / (number of segments assessed). The same segments were to be used at both baseline and post-baseline time points in the calculation of whole liver PDFF to derive the percent change from baseline. The values of whole liver PDFF ranges from 0 to 100 and higher values represent higher liver fat.
Time frame: Baseline and Week 6
Population: The efficacy analysis population was defined as all randomized participants who received at least 1 dose of randomized treatment and assessed by MRI-PDFF at Week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Whole Liver Fat at Week 6 | -7.97 Percent Change | Standard Deviation 24.521 |
| PF-06835919 75 mg | Percent Change From Baseline in Whole Liver Fat at Week 6 | 2.84 Percent Change | Standard Deviation 22.246 |
| PF-06835919 300 mg | Percent Change From Baseline in Whole Liver Fat at Week 6 | -25.43 Percent Change | Standard Deviation 22.434 |
p-value: 0.165490% CI: [-2.19, 25.09]ANCOVA
p-value: 0.039590% CI: [-33.55, -3.9]ANCOVA
Secondary
Number of Participants With Laboratory Abnormalities
Below parameters were evaluated for laboratory tests: Hemoglobin, Hematocrit, Erythrocytes, Ery. Mean Copuscular Volume, Ery. Mean Copuscular Hemoglobin, Ery. Mean Corpuscular HGB Concentration, Platelets, Leukocytes, Lymphocytes, Neuprophils, Basophils, Eosinophils, Monocytes, Bilirubin, Direct Biliirubin, Indirect Bilirubin, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase, Alkaline Phosphatase, Protein, Albumin, Albumin, Blood Urea Nitrogen, Creatinine, Urate, Sodium, Potassium, Chloride, Calcium, Bicarbonate, Glucose-Fasting, pH, Urine Glucose, Ketone, Urine Protein, Urine Hemoglobin, Urobilinogen, Urine Bilirubin, Nitrite, Leukocyte Esterase, Urine Erythocytes, Urine leukocytes, Hyaline Casts, Urine Creatinine.
Time frame: Baseline up to Day 56 (Week 8)
Population: The analysis population included participants with at least 1 observation of the given laboratory test while on study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Laboratory Abnormalities | 9 Participants |
| PF-06835919 75 mg | Number of Participants With Laboratory Abnormalities | 8 Participants |
| PF-06835919 300 mg | Number of Participants With Laboratory Abnormalities | 8 Participants |
Secondary
Number of Participants With Post-dose ECG Data Meeting Categorical Criteria
The ECG categorical criteria included: PR Interval (msec) percent (%)Change \>= 25% increase when baseline \>200 or \>=50% increase when baseline \<=200 QRS Interval (msec) %Change \>= 50% increase QTcF Interval (Fridericia's Correction) (msec) increase 30 \<= Change \< 60 or Change \>= 60 PR Interval (msec) Value \>= 300 QRS Interval (msec) Value \>= 140 QTcF Interval (Fridericia's Correction) (msec) 450 \<= Value \<480 or 480 \<=Value \<500 or Value \>= 500
Time frame: Baseline up to Day 56 (Week 8)
Population: The analysis population included all participants who received at least 1 dose of investigational product and were evaluated against the criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) Change >= 60 increase | 0 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) Value >= 500 | 1 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QRS Interval (msec) Value >= 140 | 0 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | PR Interval (msec) Value >= 300 | 0 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | PR Interval (msec) %Change >= 25/50% increase | 0 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 480<= Value < 500 | 0 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 30<= Change < 60 increase | 1 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QRS Interval (msec) %Change >= 50% increase | 0 Participants |
| Placebo | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 450 <= Value <480 | 1 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | PR Interval (msec) Value >= 300 | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | PR Interval (msec) %Change >= 25/50% increase | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QRS Interval (msec) %Change >= 50% increase | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 30<= Change < 60 increase | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) Change >= 60 increase | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QRS Interval (msec) Value >= 140 | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 450 <= Value <480 | 1 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 480<= Value < 500 | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) Value >= 500 | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 30<= Change < 60 increase | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | PR Interval (msec) %Change >= 25/50% increase | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 450 <= Value <480 | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QRS Interval (msec) %Change >= 50% increase | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) Value >= 500 | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | PR Interval (msec) Value >= 300 | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) Change >= 60 increase | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QTcF Interval (msec) 480<= Value < 500 | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose ECG Data Meeting Categorical Criteria | QRS Interval (msec) Value >= 140 | 0 Participants |
Secondary
Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria
The vital sign categorical criteria included: Sitting DBP (diastolic blood pressure) millimeter of mercury (mmHg) Change \>= 20 mmHg increase Sitting SBP (systolic blood pressure) (mmHg) Change \>= 30 mmHg increase Sitting DBP (mmHg) Change \>= 20 mmHg decrease Sitting SBP (mmHg) Change \>= 30 mmHg decrease Sitting DBP (mmHg) Value \< 50 mmHg Sitting Pulse Rate (bpm) Value \< 40 bpm or Value \> 120 bpm Sitting SBP (mmHg) Value \< 90 mmHg
Time frame: Baseline up to Day 56 (Week 8)
Population: The analysis population included all participants who received at least 1 dose of investigational product and were evaluated against the criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Change >= 20 mmHg increase | 1 Participants |
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Change >= 30 mmHg increase | 0 Participants |
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Change >= 20 mmHg decrease | 1 Participants |
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Change >= 30 mmHg decrease | 0 Participants |
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Value <50 mmHg | 0 Participants |
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting Pulse Rate (bpm) Value < 40 bpm | 0 Participants |
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting Pulse Rate (bpm) Value > 120 bpm | 0 Participants |
| Placebo | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Value < 90 mmHg | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Change >= 20 mmHg decrease | 1 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting Pulse Rate (bpm) Value > 120 bpm | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Change >= 30 mmHg decrease | 1 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Value <50 mmHg | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting Pulse Rate (bpm) Value < 40 bpm | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Change >= 20 mmHg increase | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Change >= 30 mmHg increase | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Value < 90 mmHg | 1 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Change >= 20 mmHg decrease | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Change >= 30 mmHg increase | 2 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Change >= 20 mmHg increase | 1 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Change >= 30 mmHg decrease | 2 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting Pulse Rate (bpm) Value > 120 bpm | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting Pulse Rate (bpm) Value < 40 bpm | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting DBP (mmHg) Value <50 mmHg | 0 Participants |
| PF-06835919 300 mg | Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria | Sitting SBP (mmHg) Value < 90 mmHg | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
All-causality adverse events (AEs) were any untoward medical occurrence in a study participant who administered a product or medical device, the event need not necessarily have a causal relationship with the treatment or usage. Treatment-related AEs were any untoward medical occurrence in a study participant who administered a product or medical device, the event needed to have a causal relationship with the treatment or usage. A TEAE was defined as any event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments.
Time frame: Baseline up to Day 77 (28-35 days post last dose)
Population: The safety analysis population included all participants who received at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality TEAEs | 5 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 0 Participants |
| PF-06835919 75 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality TEAEs | 4 Participants |
| PF-06835919 75 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 1 Participants |
| PF-06835919 300 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality TEAEs | 5 Participants |
| PF-06835919 300 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 1 Participants |