Hepatic ImpairmentPhase 1NCT01429337
PK and Safety of Midostaurin in Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function
A Phase 1 study testing Midostaurin in people with Hepatic Impairment, run by Novartis Pharmaceuticals at 7 sites in 6 countries.
Trial summary
The purpose of this international study was to assess the effect of varying degrees of impaired hepatic function compared to a normal hepatic function (Child-Pugh classification) on the pharmacokinetics and safety of midostaurin. Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Hepatic Impairment
- What is being tested?
- Midostaurin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 43 participants
- Where
- 7 sitesin 6 countries
- Study dates
- 7 Mar 2011to 9 May 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Adult male or female subjects age 18-70 years
- Negative serum beta-hCG pregnancy test for all women prior to starting treatment
- Normal vital signs, body weight, BMI and laboratory test results
- Willing to comply with dietary, fluid and lifestyle restrictions
- Able to communicate well with the Investigator and comply with the requirements of the study.
- Additional Inclusion Criteria for hepatic impaired subjects
Show all 10Show fewer
- Physical signs consistent with hepatic impairment
- CPC score consistent with degree of hepatic impairment
- Serum creatinine <=2xULN
- ANC >1000cells/mm3, hemaglobin >9g/dL, platelet count > 50,000/mm3 (group 2-3 only)
Who cannot join
- Significant neurologic or psychiatric disorder which could compromise participation in the study.
- History of: seizures requiring anti-convulsant therapy; unstable COPD; GI or rectal bleeding 3 weeks prior to study start; Myocardial Infarction within 12 months; unstable or poorly controlled angina or other clinically significant heart disease; clinically significant urinary obstruction or difficulty voiding; clinically significant ECG abnormalities or long QT-interval syndrome; pancreatic injury or pancreatitis
- Concurrent severe / uncontrolled medical conditions
- Significant illness within 2 weeks prior to dosing or hospitalisation within 4 weeks prior to dosing
- Any surgical or medical condition that may significantly affect absorption, distribution, metabolism or excretion of drugs
- Clinically significant ECG abnormalities at screening
Show all 20Show fewer
- Cotinine levels greater than 500ng/mL (group 1-3) or smokers not willing to limit tobacco or nicotine products equivalent to 10 cigarettes per day (group 4 and 5) for 1 week prior to dosing and throughout hospital confinement
- Consumption of alcohol within 3 days (group 1-3) or within 2 days (groups 4 and 5) prior to dosing or during the study.
- Administration of CYP3A4/5 or P-gp inducing or inhibiting drugs within 14 days prior to dosing or during the study
- Sexually active males unless they use condom during intercourse while taking midostaurin and for at least 3 months after the last exposure to drug.
- Use of any prescription drug within 2 weeks or over the counter medication within 72 hours prior to dosing
- Consumption of grapefruit, grapefruit juice, Seville oranges, start fruit / juice within 72 hours prior to dosing
- Additional exclusion criteria for healthy controls
- Clinical evidence of liver disease or liver injury
- Positive HBsAg or Hep C test result
- Additional exclusion criteria for hepatic impairment subjects
- Symptoms or history of >=G3 hepatic encephalopathy; surgical portosystemic shunt
- PTT >2.5xULN; INR >3; Total bilirubin >6mg/dL
- Evidence of progressive liver disease within 4 weeks prior to starting study
- Clinical evidence of severe >=G3 ascites (groups 2 and 3)
Trial locations and contacts
7 sites in 6 countries.
7 sites in 6 countries
Germany2 sites
Novartis Investigative Site
Berlin, 14050
Novartis Investigative Site
Frankfurt, 60590
United States1 site
American Research Corporation Inc
San Antonio, Texas, 78215
About this study
Official title: An Open-label, Parallel Group, Phase I Study to Assess the Pharmacokinetics and Safety of Midostaurin in Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function.
The purpose of this international study was to assess the effect of varying degrees of impaired hepatic function compared to a normal hepatic function (Child-Pugh classification) on the pharmacokinetics and safety of midostaurin.
Read the detailed description
Midostaurin was developed for the treatment of patients with hematological and nonhematological malignancies. However, disease complications and various co-medications made it difficult to perform a hepatic impairment study in the targeted patient population.
Metabolism and elimination of midostaurin predominantly occurs in the liver. Patients with impaired hepatic function may have a higher risk to have a decreased elimination or metabolism of midostaurin which may lead to increased systemic exposure or toxicity, hence understanding the impact of an impaired hepatic function on midostaurin PK is important.
Cumulative safety data from over 900 subjects exposed to midostaurin showed that the drug was well tolerated in patients and in healthy subjects, thus, it was appropriate and justifiable to study midostaurin in subjects with varying degrees of hepatic impairment.
Due to the difficulty in enrolling subjects with severe hepatic impairment, an interim analysis was performed when all mild and moderate hepatic impaired subjects, and the respective control subjects, had completed the trial, in order to obtain interim results on the PK and safety of midostaurin in patients with mild and moderate hepatic impairment. The protocol was amended in April 2018 to make the inclusion / exclusion criteria more fitting with enrolling the severe hepatic impairment group. The final study analysis was performed when all severe hepatic impaired subjects, and the matching controls, had completed the study.
- Conditions
- Hepatic Impairment
- Being tested
- Midostaurin
- Keywords
- Pharmacokinetics, Hepatic impaired patients, Healthy volunteers, Varying degrees of hepatic impairment
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MidostaurinDrug
Also called PKC412
Midostaurin 25 mg soft gelatin capsules (2 capsules). The midostaurin capsules will be administered orally with 240 mL of non-carbonated water in the morning (between 8-10 AM), and in the evening (after a 12 hour break) from Day 1 to Day 6. On Day 7, midostaurin will be administered in the morning only (between 8-10 AM).
MidostaurinDrug
Also called PKC412
Midostaurin 25 mg soft gelatin capsules (2 capsules). The midostaurin capsules will be administered orally with 240 mL of non-carbonated water in the morning (between 8-10 AM) on Day 1 only.
| Study group | Role | What they receive |
|---|---|---|
| Normal hepatic function - group 1 | Experimental | Matched control for group 2 and 3 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in mild and moderate hepatic function groups. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. Receives: Drug: Midostaurin |
| Mild hepatic impairment - group 2 | Experimental | Subjects with mild impaired hepatic function - Child Pugh A classification score 5-6. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. Receives: Drug: Midostaurin |
| Moderate hepatic impairment - group 3 | Experimental | Subjects with moderate hepatic function - Child Pugh B classification score 7-9. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. Receives: Drug: Midostaurin |
| Severe hepatic impairment - group 4 | Experimental | Subjects with severe hepatic impairment function - Child Pugh C classification score 10-15. Subjects will be treated with a single dose of midostaurin of 50mg on day 1. Receives: Drug: Midostaurin |
| Normal hepatic function - group 5 | Experimental | Matched control for group 4 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in severe hepatic function group. Subjects will be treated with a single dose of midostaurin of 50mg on day 1. Receives: Drug: Midostaurin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Peak Plasma Concentrations (Cmax) for midostaurin and its metabolites, CGP52421 and CGP62221
In subjects with Child Pugh A, Child Pugh B (and matching healthy volunteers) Cmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and matching healthy volunteers) Cmax will be measured at Day 1
Measured: at different timepoints from Day 1 to Day 7
Secondary outcomes (8)
Incidence of treatment emergent adverse events (AEs)
Safety and tolerability of midostaurin measured by the number of treatment emergent adverse events in subjects with hepatic impairment (and matching healthy volunteers)
Measured: During the study and until 28 days follow-up period
CYP3A4 induction by midostaurin in the hepatic impaired population
CYP3A4 induction will be measured by assessing endogenous biomarkers (6beta-hydroxycortisol to cortisol ratio) applicable to multiple dosing Child Pugh A and Child Pugh B subjects and matching healthy volunteers)
Measured: At different timepoints from Day 3 to Day 11
Protein binding (free fraction) of midostaurin and it's metabolites
Free fraction of midostaurin and it's metabolites, CGP62221 and CGP52421, will be assessed by measuring their unbound concentration in plasma samples 3 hours post last dose on Day 1 (group 4 and 5) and Day 7 (group 1-3).
Measured: Day 1 and Day 7
Apparent volume of distribution (Vz/F) of midostaurin
In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), volume of distribution will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), volume of distribution will be measured at Day 1.
Measured: Day 1 and Day 7
Total body apparent clearance of drug (CL/F) of midostaurin
In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), total body clearance will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), total body clearance will be measured at Day 1.
Measured: Day 1 and Day 7
Elimination half life (t½) of midostaurin and its metabolites, CGP52421 and CGP62221
In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), elimination half life will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), elimination half life will be measured at Day 1.
Measured: Day 1 and Day 7
Time to maximum plasma concentration (tmax) for midostaurin and its metabolites, CGP52421 and CGP62221
In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), tmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and healthy volunteers), tmax will be measured at Day 1.
Measured: Day 1 and Day 7
Area under the plasma concentration versus time curves (AUCs) for midostaurin and its metabolites, CGP52421 and CGP62221
In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), AUC will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and healthy volunteers), AUC will be measured at Day 1.
Measured: Day 1 and Day 7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Sep 2011 (estimated)
- Study start7 Mar 2011
- Primary completion13 Apr 2020
- Study completion9 May 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatic ImpairmentStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01429337
- Sponsor's protocol ID
- CPKC412A2116
- Other IDs
- 2010-020694-16
- Status last verified
- May 2021
- First submitted
- 12 Jul 2011
- Last updated
- 12 May 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Parallel Group, Phase I Study to Assess the Pharmacokinetics and Safety of Midostaurin in Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function.
- ClinicalTrials.gov ID
- NCT01429337
- Acronym / sponsor ID
- CPKC412A2116
- Conditions
- Hepatic Impairment
- Keywords
- Pharmacokinetics, Hepatic impaired patients, Healthy volunteers, Varying degrees of hepatic impairment
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 7 Mar 2011 (actual)
- Primary completion
- 13 Apr 2020 (actual)
- Study completion
- 9 May 2020 (actual)
- First posted
- 7 Sep 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this international study was to assess the effect of varying degrees of impaired hepatic function compared to a normal hepatic function (Child-Pugh classification) on the pharmacokinetics and safety of midostaurin.
Detailed description
Midostaurin was developed for the treatment of patients with hematological and nonhematological malignancies. However, disease complications and various co-medications made it difficult to perform a hepatic impairment study in the targeted patient population.
Metabolism and elimination of midostaurin predominantly occurs in the liver. Patients with impaired hepatic function may have a higher risk to have a decreased elimination or metabolism of midostaurin which may lead to increased systemic exposure or toxicity, hence understanding the impact of an impaired hepatic function on midostaurin PK is important.
Cumulative safety data from over 900 subjects exposed to midostaurin showed that the drug was well tolerated in patients and in healthy subjects, thus, it was appropriate and justifiable to study midostaurin in subjects with varying degrees of hepatic impairment.
Due to the difficulty in enrolling subjects with severe hepatic impairment, an interim analysis was performed when all mild and moderate hepatic impaired subjects, and the respective control subjects, had completed the trial, in order to obtain interim results on the PK and safety of midostaurin in patients with mild and moderate hepatic impairment. The protocol was amended in April 2018 to make the inclusion / exclusion criteria more fitting with enrolling the severe hepatic impairment group. The final study analysis was performed when all severe hepatic impaired subjects, and the matching controls, had completed the study.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Normal hepatic function - group 1 | Experimental | Drug: MidostaurinMatched control for group 2 and 3 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in mild and moderate hepatic function groups. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. |
| Mild hepatic impairment - group 2 | Experimental | Drug: MidostaurinSubjects with mild impaired hepatic function - Child Pugh A classification score 5-6. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. |
| Moderate hepatic impairment - group 3 | Experimental | Drug: MidostaurinSubjects with moderate hepatic function - Child Pugh B classification score 7-9. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7. |
| Severe hepatic impairment - group 4 | Experimental | Drug: MidostaurinSubjects with severe hepatic impairment function - Child Pugh C classification score 10-15. Subjects will be treated with a single dose of midostaurin of 50mg on day 1. |
| Normal hepatic function - group 5 | Experimental | Drug: MidostaurinMatched control for group 4 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in severe hepatic function group. Subjects will be treated with a single dose of midostaurin of 50mg on day 1. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Adult male or female subjects age 18-70 years
- Negative serum beta-hCG pregnancy test for all women prior to starting treatment
- Normal vital signs, body weight, BMI and laboratory test results
- Willing to comply with dietary, fluid and lifestyle restrictions
- Able to communicate well with the Investigator and comply with the requirements of the study.
Key exclusion criteria (20 listed)
- Significant neurologic or psychiatric disorder which could compromise participation in the study.
- History of: seizures requiring anti-convulsant therapy; unstable COPD; GI or rectal bleeding 3 weeks prior to study start; Myocardial Infarction within 12 months; unstable or poorly controlled angina or other clinically significant heart disease; clinically significant urinary obstruction or difficulty voiding; clinically significant ECG abnormalities or long QT-interval syndrome; pancreatic injury or pancreatitis
- Concurrent severe / uncontrolled medical conditions
- Significant illness within 2 weeks prior to dosing or hospitalisation within 4 weeks prior to dosing
- Any surgical or medical condition that may significantly affect absorption, distribution, metabolism or excretion of drugs
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MidostaurinAlso: PKC412Midostaurin 25 mg soft gelatin capsules (2 capsules). The midostaurin capsules will be administered orally with 240 mL of non-carbonated water in the morning (between 8-10 AM), and in the evening (after a 12 hour break) from Day 1 to Day 6. On Day 7, midostaurin will be administered in the morning only (between 8-10 AM). | Drug | Mild hepatic impairment - group 2, Moderate hepatic impairment - group 3, Normal hepatic function - group 1 |
| MidostaurinAlso: PKC412Midostaurin 25 mg soft gelatin capsules (2 capsules). The midostaurin capsules will be administered orally with 240 mL of non-carbonated water in the morning (between 8-10 AM) on Day 1 only. | Drug | Normal hepatic function - group 5, Severe hepatic impairment - group 4 |
Primary outcome
Peak Plasma Concentrations (Cmax) for midostaurin and its metabolites, CGP52421 and CGP62221
Time frame: at different timepoints from Day 1 to Day 7
In subjects with Child Pugh A, Child Pugh B (and matching healthy volunteers) Cmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and matching healthy volunteers) Cmax will be measured at Day 1
8 secondary outcomes
Incidence of treatment emergent adverse events (AEs)
Time frame: During the study and until 28 days follow-up period
CYP3A4 induction by midostaurin in the hepatic impaired population
Time frame: At different timepoints from Day 3 to Day 11
Protein binding (free fraction) of midostaurin and it's metabolites
Time frame: Day 1 and Day 7
Apparent volume of distribution (Vz/F) of midostaurin
Time frame: Day 1 and Day 7
Total body apparent clearance of drug (CL/F) of midostaurin
Time frame: Day 1 and Day 7
Elimination half life (t½) of midostaurin and its metabolites, CGP52421 and CGP62221
Time frame: Day 1 and Day 7
Time to maximum plasma concentration (tmax) for midostaurin and its metabolites, CGP52421 and CGP62221
Time frame: Day 1 and Day 7
Area under the plasma concentration versus time curves (AUCs) for midostaurin and its metabolites, CGP52421 and CGP62221
Time frame: Day 1 and Day 7
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 May 2021.
- Novartis clinical trials results databaseLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
7 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Midostaurin in people with Hepatic Impairment, run by Novartis Pharmaceuticals at 7 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Germany, United States, Belgium, Bulgaria, Lithuania and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Peak Plasma Concentrations (Cmax) for midostaurin and its metabolites, CGP52421 and CGP62221 (time frame: at different timepoints from Day 1 to Day 7). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 May 2021.