Non-alcoholic Fatty Liver Disease, Plaque Psoriasis
Conditions
Keywords
plaque psoriasis, NAFLD, NASH, PASI, secukinumab, non-alcoholic fatty liver disease
Brief summary
The aim of this study was to assess the therapeutic efficacy of secukinumab on the psoriatic skin and to explore the anti-inflammatory (reduction of hepatic inflammation and cell damage), anti-steatotic (reduction of hepatic triglyceride content) and anti-fibrotic (reduction of hepatic fibrosis) effects of secukinumab in patients with psoriasis and coexisting non-alcoholic fatty liver disease (NAFLD).
Detailed description
Primary outcome measure is Percentage of participants achieving ≥ 90% improvement (reduction) in PASI score compared to Baseline. Psoriasis Area and Severity Index (PASI) 90 response is defined as ≥ 90% improvement (reduction) in score compared to Baseline. It is a composite score where 0=no symptoms, 1=slight, 2=moderate, 3=marked, 4=very marked. Score ranges from 0 to 72, where 0 indicates no psoriasis and 72 indicates very severe psoriasis. Primary analysis was planned to be performed comparing treatments with respect to the primary efficacy variable in a logistic regression model. It was planned to present the Odds Ratio and its 95%-confidence interval and p-value. Planned null hypothesis to be rejected was that the Odds Ratio of a PASI90 response for patients with secukinumab vs. patients with placebo is ≥1 after 12 weeks. Due to premature termination and limited number of treated patients with available data (7 in the secukinumab group and 3 in the placebo group), the extent of the originally planned statistical analyses of efficacy data was limited to descriptive summaries (absolute values per visit and changes from baseline; presented as mean and SD) for the score.
Interventions
BIOLOGICALInvestigational Arm - secukinumab
secukinumab 300mg s.c. weekly in first 4 weeks, followed by q4w up to Week 20; and placebo 300mg s.c. at weeks 13, 14 and 15 to maintain the blind
BIOLOGICALControl Arm - placebo
placebo 300 mg s.c. weekly in first 4 weeks, followed by q4w up to Week 8; and secukinumab 300 mg s.c. weekly for 4 weeks starting at Week 12, followed by q4w up to Week 20
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
double-blind
Intervention model description
The primary objective of this study was to demonstrate superiority of secukinumab compared to placebo in patients with moderate to severe chronic plaque-type psoriasis and non-alcoholic fatty liver disease (NAFLD) with respect to psoriasis area and severity index (PASI) 90 response at Week 12.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male/female patients, 18 years or older * Moderate to severe plaque-type psoriasis, candidate for systemic therapy * Diagnosis of NAFLD by either ultrasound at Screening or liver histology within 6 months before Baseline * BMI \> 25 kg/ m 2 * ALT 1.2 to 3.0 × ULN * MRI confirmed Liver fat ≥ 8% at Screening
Exclusion criteria
* Forms of psoriasis other than chronic plaque-type Psoriasis * Drug induced psoriasis * Pregnant or nursing (lactating) women * Women of child bearing potential unless they are using effective methods of contraception * Ongoing use of prohibited treatments * Previous treatment with biological drug targeting IL-17 or the IL-17 receptor * Past medical history record of infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C prior to Screening * Unstable weight over the last 6 months prior to Screening. * Type I diabetes, or uncontrolled diabetes (Type I or Type II) defined as HbAlc ≥ 10% at screening. * Evidence of hepatic decompensation or severe liver impairment or cirrhosis * History of liver transplantation or planned liver transplant or biliary diversion. * Presence or history of other liver disease * Current, or history of, significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening * Prior or planned bariatric surgery * Inability or unwillingness to undergo MRI of the abdomen * Past medical history record of infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C prior to Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean and SD Change From Baseline of PASI Score up to Week 12 | 12 weeks | Psoriasis Area and Severity Index (PASI) 90 response is defined as ≥ 90% improvement (reduction) in score compared to Baseline. It is a composite score where 0=no symptoms, 1=slight, 2=moderate, 3=marked, 4=very marked. Score ranges from 0 to 72, where 0 indicates no psoriasis and 72 indicates very severe psoriasis. Primary analysis was planned to be performed comparing treatments with respect to the primary efficacy variable in a logistic regression model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Alanine Aminotransferase (ALT) Level | 12 weeks | ALT is an enzyme that the liver releases when it becomes inflamed or damaged. ALT level measures liver function Parameter. Normal range of values for ALT is about 7 to 56 units per liter (U/L). Higher levels of ALT in the blood indicate more liver problems. Due to the premature study termination and the limited number of treated patients with available data (7 patients in the secukinumab group and 3 patients in the placebo group), the extent of the originally planned statistical analyses of efficacy data was limited to descriptive summaries (absolute values per visit and changes from baseline; presented as mean and standard deviation) for the ALT score. |
| Mean and SD of DLQI at Week 12 | 12 weeks | Dermatology Life Quality Index (DLQI) is calculated by summing the score of each domain resulting in a maximum of 30 and a minimum of 0. The higher the score, the more Quality of Life was impaired. Meaning of DLQI Scores: 0-1 = no effect at all on patient's life, 2-5 = small effect on patient's life, 6-10 = moderate effect on patient's life, 11-20= very large effect on patient's life, 21-30 = extremely large effect on patient's life. Due to the premature study termination and the limited number of treated patients with available data (7 patients in the secukinumab group and 3 patients in the placebo group), the extent of the originally planned statistical analyses of efficacy data was limited to descriptive summaries (absolute values per visit and changes from baseline; presented as mean and standard deviation) for DLQI scores. |
Countries
Germany, Spain
Participant flow
Recruitment details
7 German centers and 1 Spanish center had randomized 8 and 2 patients, respectively. Patients who were still in the study when the sponsor terminated the study were counted as 'non-completers'.
Pre-assignment details
This study was prematurely discontinued after the enrollment of 10 patients, because the recruitment was too slow to achieve the planned number of patients within a reasonable time frame. No safety issues led to the decision to terminate the study prematurely.
Participants by arm
| Arm | Count |
|---|---|
| Investigational Arm - Secukinumab secukinumab 300mg s.c. weekly in first 4 weeks, followed by q4w up to Week 20; and placebo 300mg s.c. at weeks 13, 14 and 15 to maintain the blind | 7 |
| Control Arm - Placebo placebo 300 mg s.c. weekly in first 4 weeks, followed by q4w up to Week 8; and secukinumab 300 mg s.c. weekly for 4 weeks starting at Week 12, followed by q4w up to Week 20 | 3 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Study terminated by Sponsor | 4 | 1 |
Baseline characteristics
| Characteristic | Control Arm - Placebo | Investigational Arm - Secukinumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 7 Participants | 10 Participants |
| Age, Continuous | 32.0 years STANDARD_DEVIATION 16.8 | 41.6 years STANDARD_DEVIATION 11.8 | 38.7 years STANDARD_DEVIATION 13.3 |
| Race/Ethnicity, Customized White | 3 Participants | 7 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 3 |
| other Total, other adverse events | 4 / 7 | 2 / 3 |
| serious Total, serious adverse events | 1 / 7 | 0 / 3 |
Outcome results
Primary
Mean and SD Change From Baseline of PASI Score up to Week 12
Psoriasis Area and Severity Index (PASI) 90 response is defined as ≥ 90% improvement (reduction) in score compared to Baseline. It is a composite score where 0=no symptoms, 1=slight, 2=moderate, 3=marked, 4=very marked. Score ranges from 0 to 72, where 0 indicates no psoriasis and 72 indicates very severe psoriasis. Primary analysis was planned to be performed comparing treatments with respect to the primary efficacy variable in a logistic regression model.
Time frame: 12 weeks
Population: Full Analysis Set (FAS): Comprised all patients to whom study treatment/reference treatment had been assigned by randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigational Arm - Secukinumab | Mean and SD Change From Baseline of PASI Score up to Week 12 | Baseline (n=7,3) | 15.7 Units on a scale | Standard Deviation 4.22 |
| Investigational Arm - Secukinumab | Mean and SD Change From Baseline of PASI Score up to Week 12 | Week 12 (n=4,2) | 0.8 Units on a scale | Standard Deviation 1.14 |
| Control Arm - Placebo | Mean and SD Change From Baseline of PASI Score up to Week 12 | Baseline (n=7,3) | 15.9 Units on a scale | Standard Deviation 3.39 |
| Control Arm - Placebo | Mean and SD Change From Baseline of PASI Score up to Week 12 | Week 12 (n=4,2) | 13.4 Units on a scale | Standard Deviation 0.35 |
Secondary
Mean and SD of DLQI at Week 12
Dermatology Life Quality Index (DLQI) is calculated by summing the score of each domain resulting in a maximum of 30 and a minimum of 0. The higher the score, the more Quality of Life was impaired. Meaning of DLQI Scores: 0-1 = no effect at all on patient's life, 2-5 = small effect on patient's life, 6-10 = moderate effect on patient's life, 11-20= very large effect on patient's life, 21-30 = extremely large effect on patient's life. Due to the premature study termination and the limited number of treated patients with available data (7 patients in the secukinumab group and 3 patients in the placebo group), the extent of the originally planned statistical analyses of efficacy data was limited to descriptive summaries (absolute values per visit and changes from baseline; presented as mean and standard deviation) for DLQI scores.
Time frame: 12 weeks
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigational Arm - Secukinumab | Mean and SD of DLQI at Week 12 | Baseline | 11.3 Units on a scale | Standard Deviation 5.56 |
| Investigational Arm - Secukinumab | Mean and SD of DLQI at Week 12 | Week 12 | 0.3 Units on a scale | Standard Deviation 0.5 |
| Control Arm - Placebo | Mean and SD of DLQI at Week 12 | Baseline | 8.0 Units on a scale | Standard Deviation 8.49 |
| Control Arm - Placebo | Mean and SD of DLQI at Week 12 | Week 12 | 7.0 Units on a scale | Standard Deviation 8.49 |
Secondary
Serum Alanine Aminotransferase (ALT) Level
ALT is an enzyme that the liver releases when it becomes inflamed or damaged. ALT level measures liver function Parameter. Normal range of values for ALT is about 7 to 56 units per liter (U/L). Higher levels of ALT in the blood indicate more liver problems. Due to the premature study termination and the limited number of treated patients with available data (7 patients in the secukinumab group and 3 patients in the placebo group), the extent of the originally planned statistical analyses of efficacy data was limited to descriptive summaries (absolute values per visit and changes from baseline; presented as mean and standard deviation) for the ALT score.
Time frame: 12 weeks
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigational Arm - Secukinumab | Serum Alanine Aminotransferase (ALT) Level | Baseline | 60.5 U/L | Standard Deviation 35.73 |
| Investigational Arm - Secukinumab | Serum Alanine Aminotransferase (ALT) Level | Week 12 | 43.3 U/L | Standard Deviation 12.76 |
| Control Arm - Placebo | Serum Alanine Aminotransferase (ALT) Level | Baseline | 89.0 U/L | Standard Deviation 15.56 |
| Control Arm - Placebo | Serum Alanine Aminotransferase (ALT) Level | Week 12 | 85.5 U/L | Standard Deviation 20.51 |