Different Doses of BI 1467335 Compared to Placebo in Patients With Clinical Evidence of NASH
Study Details
Study Description
Brief Summary
The primary objective of this study is the proof of mechanism and support of dose finding, together with the safety evaluation in patients with clinical evidence of NASH.
To gain further insight into clinical effects of AOC3 inhibition on NASH further exploratory analyses of biomarkers related to NASH and liver fibrosis will be performed. This will include the effect of BI 1467335 on reduction of secondary biomarker endpoints (ALT, AST, AP, γ-GT and CK18 fragments). Safety will be assessed throughout the study to provide key information regarding the use of BI 1467335 in patients with NASH.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: BI 1467335 dose 1
|
Drug: BI 1467335
once daily
|
| Experimental: BI 1467335 dose 2
|
Drug: BI 1467335
once daily
|
| Experimental: BI 1467335 dose 3
|
Drug: BI 1467335
once daily
|
| Experimental: BI 1467335 dose 4
|
Drug: BI 1467335
once daily
|
| Placebo Comparator: Placebo
|
Drug: Placebo
once daily
|
Outcome Measures
Primary Outcome Measures
- Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent [Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.]
The patient-specific plasma AOC3 activity at time t (24 hours after the last dose in week 12) relative to baseline in percentage was calculated as follows: %AOC3at = [(AOC3at - AOC3at,back) ⁄ (AOC3abase - AOC3abase,back)]*100 With AOC3at the AOC3 activity measured at time t, AOC3at,back the background noise at time t, AOC3abase the AOC3 activity measured at baseline and AOC3abase,back the background noise at baseline. A dose-response relationship was analysed using a non-linear regression model to estimate the daily dosage needed to reach 10% of AOC3 activity (i.e. 90% inhibition) 12 weeks after treatment.
Secondary Outcome Measures
- Percentage of Participants With Drug-related Adverse Events (AEs) [Start of treatment till end of treatment + 28 days, up to 113 days.]
Percentage of participants with drug-related adverse events (AEs). Percentages are calculated using total number of patients per treatment as the denominator.
- Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent [Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.]
Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
- Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent [Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.]
Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
- Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent [Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.]
Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
- Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent [Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.]
Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
- Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent [Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.]
Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A MMRM over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
- Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent [Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335.]
Total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100%. Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted.
Eligibility Criteria
Criteria
Inclusion criteria:
-
Clinical evidence of NASH defined as a. histological evidence of NASH (no more than 3 years prior to screening) OR b. clinical imaging results suggestive of NASH (no more than 3 years prior to screening) OR within the screening phase, imaging procedures performed as per local standard) i. evidence of hepatic steatosis >5% measured by the MRI-PDFF) or assessed as moderate to severe steatosis (raised echogenicity of the liver parenchyma) by ultrasound AND ii. evidence of liver fibrosis defined as mean stiffness > 3.64 kPa as measured by the MRE protocol or mean stiffness > 7.2 kPa as measured by ultrasound based transient elastography (Fibroscan®)
-
Increased ALT defined as a. ALT >1.5 ULN at screening and ALT >1.25 ULN in a local lab within 1 week to 3 months prior screening OR b. Historic ALT > 1.25 ULN more than 3 months prior to screening and two consecutive ALT > 1.5xULN must be confirmed at least 1 week apart within the screening period
-
Age ≥ 18 and ≤75 years at screening
-
BMI ≥25kg/m2 and <45kg/m2 at screening
-
Stable body weight defined as less than 5% change in body weight in the 3 months prior to screening while being treated with the standard of care and not treated with anti-obesity medication at screening.
-
Treatment with Antidiabetic concomitant medication including any insulin regimen needs to be stable for 3 months, and treatment with vitamin E needs to be stable for 6 months prior to informed consent and expected to be stable throughout the trial. All other concomitant medication has to be stable for at least 4 weeks prior screening. Concomitant medications taken to treat acute conditions (e.g. headache, sinusitis) for a short period (< 7 days) are permissible, if not otherwise prohibited.
-
For female patients: Women of childbearing potential* can be randomized after a negative pregnancy test and under adequate contraception with two methods, of which at least one is highly effective, during the trial.* A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
-
Signed and dated written informed consent in accordance with GCP and local legislation prior to admission to the trial.
Exclusion criteria:
-
Current or history of significant alcohol consumption (defined as intake of >210g/week in males and >140g/week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on investigator judgement.
-
Prior participation in an interventional NASH trial 6 months before baseline or 5 times halflife of the investigational drug, whichever is longer.
-
Prior or planned bariatric surgery during study conduct, except gastric-band surgery more than 2 years prior to screening (including adjustments) with a stable body weight within the last 12 months.
-
Use of drugs historically associated with liver injury, hepatic steatosis or steatohepatitis in the 4 weeks prior to screening.
-
History of liver cirrhosis (fibrosis stage 4), or hepatic decompensation (e.g. ascites, hepatic encephalopathy, variceal bleeding, etc.) or history of other forms of chronic liver disease (for example Hepatitis B, Hepatitis C, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilsons disease, hemochromatosis, A1At deficiency, history of liver transplantation).
-
Active known chronic or relevant acute infections, such as HIV (Human Immunodeficiency Virus), \viral hepatitis, or tuberculosis. QuantiFERON® TB test and HBs Ag test will be performed during screening. Patients with a positive test result may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the patient has no evidence of active infection.
-
Solid liver lesions other than haemangiomas.
-- Suspicion or diagnosis or history of hepatocellular carcinoma (HCC)
-
eGFR <60ml/min/1.73m2 at screening (CKD-EPI formula).
-
ALT >5.0 ULN at screening.
-
Platelet count < 150.000/μL
-
Bilirubin level > ULN (except for known Gilbert´s disease with a conjugated bilirubin of < 0.3 mg/dL))
-
Uncontrolled diabetes defined as an HbA1c ≥9.5% in the 3 months prior to or at screening.
-
Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic , psychiatric, immunologic, or hematologic disease and other conditions that, in the clinical judgment of the investigator, are likely to interfere with the analyses of safety and efficacy in this study. Patients with an expected life expectancy of less than 2 years are also excluded.
-
Major surgery (major according to the investigator's assessment) performed within 12 weeks prior to randomisation or planned during study conduct, e.g. hip replacement.
-
Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.
-
Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
-
Previous randomisation in this trial.
-
Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s).
-
Chronic drug abuse or any condition that, in the investigator's opinion, makes them an unreliable study subject or unlikely to complete the trial.
-
Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
-
Patients with Wolff-Parkinson-White Syndrome, baseline QTc > 450 ms, family history of long QT, or on medication prolonging QT time at screening or planned initiation during the trial.
-
Any other clinical condition that, in the opinion of the investigator, would jeopardize patient safety while participating in this clinical trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Southern California Research Center | Coronado | California | United States | 92118 |
| 2 | University of California San Diego | La Jolla | California | United States | 92037 |
| 3 | eStudySite | La Mesa | California | United States | 91942 |
| 4 | National Research Institute | Los Angeles | California | United States | 90057 |
| 5 | National Research Institute | Los Angeles | California | United States | 90255 |
| 6 | Quest Clinical Research | San Francisco | California | United States | 94115 |
| 7 | Florida Research Institute | Lakewood Ranch | Florida | United States | 34211 |
| 8 | Genoma Research Group, Inc | Miami | Florida | United States | 33165 |
| 9 | Rutgers Robert Wood Johnson Medical School | New Brunswick | New Jersey | United States | 08901 |
| 10 | Northwell Health | Manhasset | New York | United States | 11030 |
| 11 | The University of North Carolina at Chapel Hill | Chapel Hill | North Carolina | United States | 27599 |
| 12 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 13 | Diabetes and Endocrinology Consultants, PC | Morehead City | North Carolina | United States | 28557 |
| 14 | Dallas Diabetes and Endocrine Center | Dallas | Texas | United States | 75230 |
| 15 | Pinnacle Clinical Research | Live Oak | Texas | United States | 78233 |
| 16 | American Research Corporation at the Texas Liver Institute | San Antonio | Texas | United States | 78215 |
| 17 | Virginia Commonwealth University | Richmond | Virginia | United States | 23298 |
| 18 | Edegem - UNIV UZ Antwerpen | Edegem | Belgium | 2650 | |
| 19 | AZ Maria Middelares | Gent | Belgium | 9000 | |
| 20 | UZ Leuven | Leuven | Belgium | 3000 | |
| 21 | Centre Hospitalier Universitaire de Liège | Liège | Belgium | 4000 | |
| 22 | University of Calgary | Calgary | Alberta | Canada | T2N 4Z6 |
| 23 | Toronto Liver Centre | Toronto | Ontario | Canada | M6H 3M1 |
| 24 | HOP Claude Huriez | Lille | France | 59037 | |
| 25 | HOP La Pitié Salpêtrière | Paris | France | 75651 | |
| 26 | Universitätsklinikum Aachen, AöR | Aachen | Germany | 52074 | |
| 27 | Universitätsklinikum Frankfurt | Frankfurt am Main | Germany | 60590 | |
| 28 | Universitätsklinikum Köln (AöR) | Köln | Germany | 50937 | |
| 29 | Universitätsklinikum Leipzig | Leipzig | Germany | 04103 | |
| 30 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz | Mainz | Germany | 55131 | |
| 31 | Universitätsklinikum Würzburg | Würzburg | Germany | 97080 | |
| 32 | St James's Hospital | Dublin | Ireland | 8 | |
| 33 | Amsterdam UMC, Locatie AMC | Amsterdam | Netherlands | 1105 AZ | |
| 34 | Maastricht Universitair Medisch Centrum | Maastricht | Netherlands | 6229 HX | |
| 35 | Radboud Universitair Medisch Centrum | Nijmegen | Netherlands | 6525 GA | |
| 36 | Hospital Vall d'Hebron | Barcelona | Spain | 08035 | |
| 37 | Hospital Virgen de la Victoria | Malaga | Spain | 29010 | |
| 38 | Hospital Universitario Marqués de Valdecilla | Santander | Spain | 39008 | |
| 39 | Hospital Virgen del Rocío | Sevilla | Spain | 41013 | |
| 40 | Hospital General Universitario de Valencia | Valencia | Spain | 46014 | |
| 41 | Queen Elizabeth Hospital | Birmingham | United Kingdom | B15 2TH | |
| 42 | Aintree University Hospital | Liverpool | United Kingdom | L9 7AL | |
| 43 | Manchester Royal Infirmary | Manchester | United Kingdom | M13 9WL | |
| 44 | Royal Stoke University Hospital | Stoke on Trent | United Kingdom | ST4 6QG |
Sponsors and Collaborators
- Boehringer Ingelheim
Investigators
None specified.Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 1386-0004
- 2016-000499-83
Study Results
Participant Flow
| Recruitment Details | This study is a multi-centre, double-blind, parallel-group, randomised, placebo-controlled phase IIa study to investigate safety, tolerability, pharmacodynamics, and pharmacokinetics of different doses of orally administered BI 1467335 (for 12-weeks) compared to placebo in patients with clinical evidence of Non-alcoholic steato-hepatitis (NASH). |
|---|---|
| Pre-assignment Detail | All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Period Title: Overall Study | |||||
| STARTED | 33 | 16 | 16 | 17 | 32 |
| Treated | 32 | 16 | 16 | 17 | 32 |
| COMPLETED | 32 | 13 | 13 | 16 | 28 |
| NOT COMPLETED | 1 | 3 | 3 | 1 | 4 |
Baseline Characteristics
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) | Total |
|---|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | Total of all reporting groups |
| Overall Participants | 32 | 16 | 16 | 17 | 32 | 113 |
| Age (years) [Mean (Standard Deviation) ] | ||||||
| Mean (Standard Deviation) [years] |
51.8
(12.3)
|
52.6
(13.3)
|
53.9
(11.5)
|
48.2
(10.1)
|
49.8
(14.0)
|
51.1
(12.5)
|
| Sex: Female, Male (Count of Participants) | ||||||
| Female |
13
40.6%
|
10
62.5%
|
8
50%
|
9
52.9%
|
18
56.3%
|
58
51.3%
|
| Male |
19
59.4%
|
6
37.5%
|
8
50%
|
8
47.1%
|
14
43.8%
|
55
48.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||||
| Hispanic or Latino |
11
34.4%
|
5
31.3%
|
5
31.3%
|
4
23.5%
|
8
25%
|
33
29.2%
|
| Not Hispanic or Latino |
21
65.6%
|
11
68.8%
|
11
68.8%
|
13
76.5%
|
24
75%
|
80
70.8%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
1
3.1%
|
1
6.3%
|
0
0%
|
0
0%
|
0
0%
|
2
1.8%
|
| Native Hawaiian or Other Pacific Islander |
1
3.1%
|
1
6.3%
|
0
0%
|
0
0%
|
0
0%
|
2
1.8%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
30
93.8%
|
14
87.5%
|
16
100%
|
17
100%
|
32
100%
|
109
96.5%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Plasma amine oxidase copper-containing 3 (AOC3) baseline concentration (microgram per liter (µg/l)) [Mean (Standard Deviation) ] | ||||||
| Mean (Standard Deviation) [microgram per liter (µg/l)] |
471.4063
(165.6802)
|
537.7143
(204.4100)
|
498.0000
(141.0225)
|
527.2941
(142.3722)
|
516.1613
(144.0727)
|
504.9636
(157.4936)
|
Outcome Measures
| Title | Plasma Amine Oxidase Copper-containing 3 (AOC3) Activity After 12 Weeks of Treatment, Relative to Baseline in Percent |
|---|---|
| Description | The patient-specific plasma AOC3 activity at time t (24 hours after the last dose in week 12) relative to baseline in percentage was calculated as follows: %AOC3at = [(AOC3at - AOC3at,back) ⁄ (AOC3abase - AOC3abase,back)]*100 With AOC3at the AOC3 activity measured at time t, AOC3at,back the background noise at time t, AOC3abase the AOC3 activity measured at baseline and AOC3abase,back the background noise at baseline. A dose-response relationship was analysed using a non-linear regression model to estimate the daily dosage needed to reach 10% of AOC3 activity (i.e. 90% inhibition) 12 weeks after treatment. |
| Time Frame | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 30 | 12 | 14 | 11 | 24 |
| Mean (Standard Deviation) [Percentage relative to baseline] |
102
(13.0)
|
24.0
(11.9)
|
13.1
(10.4)
|
8.27
(5.19)
|
2.06
(3.62)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, BI 1467335 1 Milligram (mg), BI 1467335 3 Milligram (mg), BI 1467335 6 Milligram (mg), BI 1467335 10 Milligram (mg) |
|---|---|---|
| Comments | D10: Estimated dose reaching <=10% activity the first time. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Predicted mean daily dose in mg |
| Estimated Value | 3.45 | |
| Confidence Interval |
() % to |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.10 |
|
| Estimation Comments | The model fit used power of mean variance estimates (POM) to account for heterogeneity. | |
| Title | Percentage of Participants With Drug-related Adverse Events (AEs) |
|---|---|
| Description | Percentage of participants with drug-related adverse events (AEs). Percentages are calculated using total number of patients per treatment as the denominator. |
| Time Frame | Start of treatment till end of treatment + 28 days, up to 113 days. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated Set (TS): All patients who signed the informed consent and were treated with at least one dose of the trial medication. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 32 | 16 | 16 | 17 | 32 |
| Number [Percentage of participants] |
25.0
78.1%
|
31.3
195.6%
|
12.5
78.1%
|
11.8
69.4%
|
25.0
78.1%
|
| Title | Alanine Aminotransaminase (ALT) After 12 Weeks of Treatment, Relative to Baseline in Percent |
|---|---|
| Description | Alanine aminotransaminase (ALT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Time Frame | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 28 | 12 | 13 | 14 | 27 |
| Mean (Standard Error) [Percentage relative to baseline] |
92.66
(106.55)
|
97.32
(110.13)
|
87.49
(109.79)
|
80.61
(109.43)
|
77.57
(106.66)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, BI 1467335 1 Milligram (mg), BI 1467335 3 Milligram (mg), BI 1467335 6 Milligram (mg), BI 1467335 10 Milligram (mg) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod. | |
| Statistical Test of Hypothesis | p-Value | 0.0212 |
| Comments | p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose-response curve) with alpha 0.05, one-sided. | |
| Method | MCPMod Sigmoidal Emax model fit. | |
| Comments | 30% of the maximum effect is achieved at 3 mg and 90% of the maximum effect is achieved at 7 mg of BI 1467335 | |
| Title | Aspartate Aminotransferase (AST) After 12 Weeks of Treatment, Relative to Baseline in Percent |
|---|---|
| Description | Aspartate aminotransferase (AST) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Time Frame | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 27 | 12 | 13 | 14 | 23 |
| Mean (Standard Error) [Percentage relative to baseline] |
93.77
(105.91)
|
105.17
(108.93)
|
90.09
(108.72)
|
84.12
(108.34)
|
87.83
(106.26)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, BI 1467335 1 Milligram (mg), BI 1467335 3 Milligram (mg), BI 1467335 6 Milligram (mg), BI 1467335 10 Milligram (mg) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod. | |
| Statistical Test of Hypothesis | p-Value | 0.1270 |
| Comments | p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose-response curve) with alpha 0.05, one-sided. | |
| Method | MCPMod Sigmoidal Emax model fit. | |
| Comments | 30% of the maximum effect is achieved at 3 mg and 90% of the maximum effect is achieved at 7 mg of BI 1467335 | |
| Title | Alkaline Phosphatase (AP) After 12 Weeks of Treatment, Relative to Baseline in Percent |
|---|---|
| Description | Alkaline phosphatase (AP) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Time Frame | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 29 | 12 | 13 | 14 | 28 |
| Mean (Standard Error) [Percentage relative to baseline] |
96.62
(102.31)
|
97.58
(103.56)
|
100.52
(103.45)
|
98.47
(103.34)
|
94.71
(102.34)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, BI 1467335 1 Milligram (mg), BI 1467335 3 Milligram (mg), BI 1467335 6 Milligram (mg), BI 1467335 10 Milligram (mg) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod. | |
| Statistical Test of Hypothesis | p-Value | 0.3324 |
| Comments | p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose-response curve) with alpha 0.05, one-sided. | |
| Method | MCPMod exponential model fit. | |
| Comments | 90% of the maximum effect is achieved at 7 mg of BI 1467335 | |
| Title | Gamma-glutamyltransferase (GGT) After 12 Weeks of Treatment, Relative to Baseline in Percent |
|---|---|
| Description | Gamma-glutamyltransferase (GGT) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Time Frame | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 29 | 12 | 13 | 14 | 28 |
| Mean (Standard Error) [Percentage relative to baseline] |
91.37
(105.24)
|
99.42
(108.25)
|
92.44
(108.09)
|
99.51
(107.71)
|
83.70
(105.40)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, BI 1467335 1 Milligram (mg), BI 1467335 3 Milligram (mg), BI 1467335 6 Milligram (mg), BI 1467335 10 Milligram (mg) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod. | |
| Statistical Test of Hypothesis | p-Value | 0.1290 |
| Comments | p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose-response curve) with alpha 0.05, one-sided. | |
| Method | MCPMod exponential model fit. | |
| Comments | 90% of the maximum effect is achieved at 7 mg of BI 1467335 | |
| Title | Caspase-cleaved Cytokeratin 18 (CK-18 Caspase) After 12 Weeks of Treatment, Relative to Baseline in Percent |
|---|---|
| Description | Caspase-cleaved cytokeratin 18 (CK-18 caspase) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100% Statistical analyses description: A MMRM over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Time Frame | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Set (PPS): Patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 29 | 12 | 12 | 14 | 26 |
| Mean (Standard Error) [Percentage relative to baseline] |
101.35
(111.15)
|
155.04
(117.61)
|
96.87
(117.54)
|
80.51
(116.32)
|
78.08
(111.59)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, BI 1467335 1 Milligram (mg), BI 1467335 3 Milligram (mg), BI 1467335 6 Milligram (mg), BI 1467335 10 Milligram (mg) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod. | |
| Statistical Test of Hypothesis | p-Value | 0.0042 |
| Comments | p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose-response curve) with alpha 0.05, one-sided. | |
| Method | MCPMod Sigmoidal Emax model fit. | |
| Comments | 30% of the maximum effect is achieved at 3 mg and 90% of the maximum effect is achieved at 7 mg of BI 1467335 | |
| Title | Total Cytokeratin 18 (CK-18 Total) After 12 Weeks of Treatment, Relative to Baseline in Percent |
|---|---|
| Description | Total cytokeratin 18 (CK-18 total) after 12 weeks of treatment, relative to baseline in percent. Number analyzed lower than N in PPS if there is missing data for specific timepoints. The unit of measure is: percentage relative to baseline = [post baseline (time t)/baseline]*100%. Statistical analyses description: A Mixed effects Model for Repeated Measurements (MMRM) over time including fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction was performed. The MMRM estimates for the treatment effects at Week 12 and the corresponding covariance matrix were used to analyse the dose-response relationship using the Multiple contrast test (MCPMod). A test for non-flat dose-response relationship was first performed. If this relationship could be shown, the best fitting model out of a set of candidate models (Sigmoidal Emax, Logistic, Quadratic, Linear, Exponential, Linear logistic, Emax and Betamod) was to be selected and fitted. |
| Time Frame | Day 1 (baseline), day 15, 29, 43, 57 and 85 (time t) 24 hours after the last dose of BI 1467335. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Set (PPS): patients who signed informed consent, were treated with at least one dose of the trial medication, without any important protocol deviations leading to exclusion and who had non-missing baseline and at least one non-missing post-baseline and on-treatment measurement on any primary, secondary or further biomarker endpoint. |
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) |
|---|---|---|---|---|---|
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. |
| Measure Participants | 28 | 11 | 13 | 14 | 26 |
| Mean (Standard Error) [Percentage relative to baseline] |
92.44
(109.13)
|
128.33
(114.64)
|
99.56
(113.78)
|
94.74
(113.10)
|
81.47
(109.35)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, BI 1467335 1 Milligram (mg), BI 1467335 3 Milligram (mg), BI 1467335 6 Milligram (mg), BI 1467335 10 Milligram (mg) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | The MMRM included fixed effects for 'base', 'treatment', 'time', 'base*time' interaction, and 'treatment*time' interaction. Estimates were used to test dose-response relationship using MCPMod. | |
| Statistical Test of Hypothesis | p-Value | 0.0728 |
| Comments | p<0.05 is a significant test result (rejecting the null hypothesis of a flat dose-response curve) with alpha 0.05, one-sided. | |
| Method | MCPMod exponential model fit. | |
| Comments | 90% of the maximum effect is achieved at 7 mg of BI 1467335 | |
Adverse Events
| Time Frame | start of treatment till end of treatment + 28 days, up to 113 days. | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse events are reported based on the Treated Set (all patients who signed the informed consent and were treated with at least one dose of the trial medication). | |||||||||||
| Arm/Group Title | Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) | Total BI 1467335 | ||||||
| Arm/Group Description | Matching placebo taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated placebo tablets were supplied. For blinding reasons, all patients took 5 tablets placebo daily. | 1 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 3 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 6 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | 10 milligram (mg) BI 1467335 taken daily for 12 weeks. Tablets taken orally with water in the morning, fasted, 1 hour before breakfast. Film-coated tablets were supplied as 1 mg and 5 mg dose strengths. For blinding reasons, all patients took 5 tablets verum or placebo daily. | All participant who took a dose of BI 1467335. | ||||||
All Cause Mortality |
||||||||||||
| Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) | Total BI 1467335 | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 0/81 (0%) | ||||||
Serious Adverse Events |
||||||||||||
| Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) | Total BI 1467335 | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/32 (3.1%) | 1/16 (6.3%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Pancreatitis | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Infections and infestations | ||||||||||||
| H1N1 influenza | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Sinusitis | 1/32 (3.1%) | 0/16 (0%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 0/81 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Acute respiratory failure | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Chronic obstructive pulmonary disease | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Nasal septum deviation | 1/32 (3.1%) | 0/16 (0%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 0/81 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
| Placebo | BI 1467335 1 Milligram (mg) | BI 1467335 3 Milligram (mg) | BI 1467335 6 Milligram (mg) | BI 1467335 10 Milligram (mg) | Total BI 1467335 | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 18/32 (56.3%) | 12/16 (75%) | 12/16 (75%) | 13/17 (76.5%) | 17/32 (53.1%) | 54/81 (66.7%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Vertigo | 2/32 (6.3%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 1/32 (3.1%) | 2/81 (2.5%) | ||||||
| Eye disorders | ||||||||||||
| Vision blurred | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Abdominal discomfort | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Abdominal pain | 1/32 (3.1%) | 1/16 (6.3%) | 0/16 (0%) | 1/17 (5.9%) | 1/32 (3.1%) | 3/81 (3.7%) | ||||||
| Abdominal pain lower | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Abdominal pain upper | 1/32 (3.1%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Diarrhoea | 3/32 (9.4%) | 1/16 (6.3%) | 1/16 (6.3%) | 2/17 (11.8%) | 3/32 (9.4%) | 7/81 (8.6%) | ||||||
| Dry mouth | 1/32 (3.1%) | 1/16 (6.3%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Dyspepsia | 1/32 (3.1%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 2/32 (6.3%) | 3/81 (3.7%) | ||||||
| Flatulence | 1/32 (3.1%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Gastrooesophageal reflux disease | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 1/32 (3.1%) | 2/81 (2.5%) | ||||||
| Nausea | 1/32 (3.1%) | 4/16 (25%) | 1/16 (6.3%) | 0/17 (0%) | 5/32 (15.6%) | 10/81 (12.3%) | ||||||
| Pouchitis | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Toothache | 2/32 (6.3%) | 0/16 (0%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 0/81 (0%) | ||||||
| Vomiting | 0/32 (0%) | 2/16 (12.5%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| General disorders | ||||||||||||
| Asthenia | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Chest pain | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Early satiety | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Fatigue | 3/32 (9.4%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 5/32 (15.6%) | 6/81 (7.4%) | ||||||
| Influenza like illness | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Pain | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 0/17 (0%) | 2/32 (6.3%) | 2/81 (2.5%) | ||||||
| Hepatobiliary disorders | ||||||||||||
| Hepatic pain | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Immune system disorders | ||||||||||||
| Hypersensitivity | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 1/17 (5.9%) | 1/32 (3.1%) | 3/81 (3.7%) | ||||||
| Infections and infestations | ||||||||||||
| Bronchitis | 1/32 (3.1%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Gastroenteritis | 2/32 (6.3%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Gastroenteritis bacterial | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Influenza | 0/32 (0%) | 2/16 (12.5%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Nasopharyngitis | 3/32 (9.4%) | 3/16 (18.8%) | 2/16 (12.5%) | 1/17 (5.9%) | 5/32 (15.6%) | 11/81 (13.6%) | ||||||
| Otitis media | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Rhinitis | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Sinusitis | 1/32 (3.1%) | 0/16 (0%) | 1/16 (6.3%) | 1/17 (5.9%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Tooth abscess | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Tooth infection | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Upper respiratory tract infection | 2/32 (6.3%) | 0/16 (0%) | 1/16 (6.3%) | 1/17 (5.9%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Urinary tract infection | 2/32 (6.3%) | 2/16 (12.5%) | 0/16 (0%) | 0/17 (0%) | 1/32 (3.1%) | 3/81 (3.7%) | ||||||
| Viral upper respiratory tract infection | 1/32 (3.1%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Concussion | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Ligament sprain | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 1/32 (3.1%) | 2/81 (2.5%) | ||||||
| Post-traumatic neck syndrome | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Road traffic accident | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Tooth fracture | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Vascular procedure complication | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Investigations | ||||||||||||
| Blood creatine phosphokinase increased | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Blood glucose increased | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Gamma-glutamyltransferase increased | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Lipase increased | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Weight increased | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Metabolism and nutrition disorders | ||||||||||||
| Decreased appetite | 1/32 (3.1%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 1/32 (3.1%) | 2/81 (2.5%) | ||||||
| Diabetes mellitus inadequate control | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Hyperlipidaemia | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Hypertriglyceridaemia | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Type 2 diabetes mellitus | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Back pain | 1/32 (3.1%) | 2/16 (12.5%) | 1/16 (6.3%) | 0/17 (0%) | 1/32 (3.1%) | 4/81 (4.9%) | ||||||
| Muscular weakness | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Neck pain | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 2/17 (11.8%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Anogenital warts | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Nervous system disorders | ||||||||||||
| Disturbance in attention | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Dizziness | 0/32 (0%) | 1/16 (6.3%) | 2/16 (12.5%) | 0/17 (0%) | 3/32 (9.4%) | 6/81 (7.4%) | ||||||
| Headache | 4/32 (12.5%) | 3/16 (18.8%) | 0/16 (0%) | 4/17 (23.5%) | 2/32 (6.3%) | 9/81 (11.1%) | ||||||
| Sciatica | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Tension headache | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Psychiatric disorders | ||||||||||||
| Anxiety | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 1/17 (5.9%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Nephrolithiasis | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Cough | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 1/32 (3.1%) | 2/81 (2.5%) | ||||||
| Dry throat | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Epistaxis | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 1/17 (5.9%) | 0/32 (0%) | 2/81 (2.5%) | ||||||
| Paranasal sinus discomfort | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Rhinitis allergic | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Sinus pain | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 1/17 (5.9%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Rash | 0/32 (0%) | 0/16 (0%) | 0/16 (0%) | 0/17 (0%) | 2/32 (6.3%) | 2/81 (2.5%) | ||||||
| Rash erythematous | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Rash papular | 0/32 (0%) | 1/16 (6.3%) | 0/16 (0%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Vascular disorders | ||||||||||||
| Orthostatic hypotension | 1/32 (3.1%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
| Subclavian steal syndrome | 0/32 (0%) | 0/16 (0%) | 1/16 (6.3%) | 0/17 (0%) | 0/32 (0%) | 1/81 (1.2%) | ||||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
| Name/Title | Boehringer Ingelheim, Call Center |
|---|---|
| Organization | Boehringer Ingelheim |
| Phone | 1-800-243-0127 |
| clintriage.rdg@boehringer-ingelheim.com |
- 1386-0004
- 2016-000499-83