AtherosclerosisPhase 1NCT01711723
A Study to Assess the Pharmacokinetics, Safety and Tolerability of Repeat Oral Doses of Darapladib (SB-480848) in Subjects With Severe Renal Impairment
A Phase 1 study testing Darapladib 160 mg in people with Atherosclerosis, run by GlaxoSmithKline at 2 sites in United States.
Trial summary
In accordance with the recently revised FDA draft renal impairment guidance (March 2010) which advises the conduct of renal impairment study in drugs that are not predominately eliminated through the renal route, the proposed study will be conducted to formally assess the pharmacokinetics (PK) of darapladib in… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Atherosclerosis
- What is being tested?
- Darapladib 160 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 2 sitesUnited States
- Study dates
- 29 Oct 2012to 25 Mar 2013
- 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 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- A male or female is eligible to enter and participate in this study if he/she is: A healthy subject with normal renal function: Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with clinical abnormalities or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures; Estimated Creatinine clearance ≥ 90mL/min calculated by Cockcroft-Gault equation using serum creatinine OR A renally impaired subject - To be classified as renally impaired, subjects must have: An estimated Glomerular Filtration Rate (eGFR) of <30 ml/min /1.73 m2 using the four variable Modification of Diet in Renal Disease (MDRD) equation.
- Age between 18 and 75 years inclusive, at the time of signing the informed consent.
- A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140pmol/L) is confirmatory]; Child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the final follow-up visit (35 ± 7 days after last dose of investigational product)
- Body mass index (BMI) within the range of 19.0-38.0 kg/m2 (inclusive)
- Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- QTcF ≤ 480 msec in all subjects, including those with bundle branch block at screening ECG.
Who cannot join
- Healthy Subjects
- A positive pre-study drug/alcohol screen.
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody or positive Hepatitis A IGM antibody result within 3 months of screening.
- A positive test for HIV antibody.
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones
- History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
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- The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, or 5 half-lives of the investigational product (whichever is longer).
- Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St. John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
- Requiring the use of oral or injectable strong CYP3A4 inhibitors (refer to the protocol).
- Consumption of grapefruit or grapefruit juice > 8oz within 7 days prior to first dose of study medication.
- Drug abuse within the past 6 months, or current mental condition (psychiatric disorder, senility or dementia), which may affect study compliance or prevent understanding of the aims, investigational procedures or possible consequences of the study.
- History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
- History of anaphylaxis, or anaphylactoid (resembling anaphylaxis) reactions (refer to the protocol). History of severe allergic responses.
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
- Use of oral, injected and implanted hormonal methods of contraception for female subjects.
- Pregnant females as determined by positive serum hCG test at screening or prior to dosing.
- Lactating females.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Subjects with a risk of non-compliance in following directions or adhering to study instructions, or any subject that the principal investigator deems unsuitable for participation or continuation.
- Renally Impaired Subjects
- Subjects with a life expectancy less than 3 months.
- Anticipated need for dialysis during the study.
- A positive pre-study drug/alcohol screen, except where subject has a prescription for pain or anxiolytic medication that would cause a positive test. Investigator should consult medical monitor with patient history before screening if it is known that a patient could have positive test.
- Subjects with a positive HIV antibody test.
- Subjects using any concurrent prohibited medication, and/or receiving concurrent therapy that cannot be safely discontinued and is not approved by the Investigator (see protocol for details on prohibited medications).
- Cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), unstable liver disease (defined by the presence of any of the following felt by the investigator to be related to liver disease and not to other disease processes: ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice), or evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase >1.5 x upper limit of normal [ULN]; or ALT >2.5 x ULN) or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
- Severe asthma that is poorly controlled on pharmacotherapy.
- The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- Requiring the use of oral or injectable strong CYP3A4 inhibitors (refer to protocol). Consumption of grapefruit or grapefruit juice within 7 days prior to first dose of study medication
- If in the opinion of the Investigator there is an unstable cardiovascular, pulmonary, or hepatic condition present, or any other medical condition which the Investigator and the Medical Monitor considers sufficiently serious to interfere with the conduct, completion, or result of this trial or constitutes an unacceptable risk to the subject.
- History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
- History of anaphylaxis, or anaphylactoid (resembling anaphylaxis) reactions (refer to the protocol. History of severe allergic responses.
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
- Use of oral, injected and implanted hormonal methods of contraception for female subjects.
- Pregnant females as determined by positive serum hCG test at screening or prior to dosing.
- Lactating females
- History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
- Subjects with a risk of non-compliance in following directions or adhering to study restrictions, or any subject that the principal investigator deems unsuitable for participation or continuation.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
GSK Investigational Site
Minneapolis, Minnesota, 55404
GSK Investigational Site
Orlando, Florida, 32809
About this study
Official title: An Open-Label, Non-Randomized, Pharmacokinetic and Safety Study of Multiple Oral Doses of SB-480848 in Healthy Subjects and in Subjects With Severe Renal Impairment
In accordance with the recently revised FDA draft renal impairment guidance (March 2010) which advises the conduct of renal impairment study in drugs that are not predominately eliminated through the renal route, the proposed study will be conducted to formally assess the pharmacokinetics (PK) of darapladib in severely renally impaired subjects.
In this is an open-label, non-randomized study eight subjects with severe renal impairment will be recruited along with 8 healthy control subjects matched to the severe renal impairment subjects based on gender, body mass index (plus or minus 20%) and age (plus or minus 10 years).
Read more
All subjects will receive repeat oral doses of darapladib 160 milligram (mg) for 10 consecutive days. The pharmacokinetics of darapladib and its metabolites; and safety and tolerability will be evaluated.
All the subjects will be admitted to the clinic on the evening of Day -1. Subjects may check out of the clinic on Day 2 after all assessments are complete, but must return to the clinic each day (Days 3-8) for dosing and assessments. Subjects will be admitted to the clinic again on the evening of Day 9. After the last dose of the study drug, there will be a follow-up period which will include 2 visits (Day 20-24 and Day 38-52). The total study duration for each subject including the screening, treatment and follow-up periods will be approximately 11 weeks.
- Conditions
- Atherosclerosis
- Being tested
- Darapladib 160 mg
- Keywords
- darapladib, Lp-PLA2- inhibitor, healthy volunteer, renal impairment, pharmacokinetics
- Medical subject headings
- Atherosclerosis, Renal Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Darapladib 160 mgDrug
Subjects in each group received one tablet orally of Darapladib 160 mg daily for 10 consecutive days. Tablets were taken with food, swallowed whole, not chewed.
| Study group | Role | What they receive |
|---|---|---|
| Renal Impaired Group | Experimental | Subjects with renal impairment received darapladip 160 mg daily for 10 consecutive days. Receives: Drug: Darapladib 160 mg |
| Healthy Control Group | Experimental | Healthy volunteers matching with renal impairment subjects for gender, age and BMI; received darapladip 160 mg daily for 10 consecutive days. Receives: Drug: Darapladib 160 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
AUC (0-τ) for darapladib and as data permit for metabolites M4, M3, and M10
The PK parameter area under the concentration-time curve over the dosing interval (AUC (0-τ)) will be derived from the plasma concentration-time data.
Measured: On scheduled intervals on Day 10
Cmax for darapladib and as data permit for metabolite s M4, M3, and M10
The PK parameter maximum observed concentration (Cmax) will be derived from the plasma concentration-time data.
Measured: On scheduled intervals on Day 10
Secondary outcomes (6)
Spontaneous AE reporting
Adverse events (AEs) will be collected from the start of Investigation Product and until the follow-up visit.
Measured: 45days
Clinical laboratory test measurements
Clinical laboratory tests will include hematology, clinical chemistry and urinalysis.
Measured: Day-1, Day 11 and post treatment
Vital signs measurements
Vital sign measurements will include systolic and diastolic blood pressure and pulse rate. Subjects should have been resting quietly in a supine or semi-supine (recumbent) position for at least 10 minutes prior to taking measurements.
Measured: Day-1, Day1, Day5, Day 11 and post treatment
Nursing/physician observation
The physical examination will include assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).
Measured: 20 days
Free fraction (% unbound) of darapladib and its metabolites M3, M4, and M10 (as data permit)
Concentrations of darapladib, M4, M3 and M10 will be determined in plasma samples using the currently approved analytical methodology. Attempts will be made to determine the unbound fraction of darapladib and its metabolites.
Measured: On scheduled intervals on Day 10
Tmax and t1/2 of darapladib and its metabolites M3, M4, M3, and M10 (as data permit)
The PK parameters Tmax (time of occurrence of Cmax) and t1/2 (terminal phase half-life) will be derived from the plasma concentration-time data for darapladib and its metabolites M3, M4, M3, and M10.
Measured: On scheduled intervals on Day 10
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Oct 2012 (estimated)
- Study start29 Oct 2012
- Primary completion25 Mar 2013
- Study completion25 Mar 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AtherosclerosisStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe 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
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01711723
- Sponsor's protocol ID
- 115676
- Status last verified
- Jul 2017
- First submitted
- 18 Oct 2012
- Last updated
- 26 Jul 2017
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Study at a glance
From the registry record, last updated by the sponsor on 26 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, Non-Randomized, Pharmacokinetic and Safety Study of Multiple Oral Doses of SB-480848 in Healthy Subjects and in Subjects With Severe Renal Impairment
- ClinicalTrials.gov ID
- NCT01711723
- Acronym / sponsor ID
- 115676
- Conditions
- Atherosclerosis
- Keywords
- darapladib, Lp-PLA2- inhibitor, healthy volunteer, renal impairment, pharmacokinetics
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 29 Oct 2012 (actual)
- Primary completion
- 25 Mar 2013 (actual)
- Study completion
- 25 Mar 2013 (actual)
- First posted
- 22 Oct 2012 (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.
In accordance with the recently revised FDA draft renal impairment guidance (March 2010) which advises the conduct of renal impairment study in drugs that are not predominately eliminated through the renal route, the proposed study will be conducted to formally assess the pharmacokinetics (PK) of darapladib in severely renally impaired subjects.
In this is an open-label, non-randomized study eight subjects with severe renal impairment will be recruited along with 8 healthy control subjects matched to the severe renal impairment subjects based on gender, body mass index (plus or minus 20%) and age (plus or minus 10 years).
All subjects will receive repeat oral doses of darapladib 160 milligram (mg) for 10 consecutive days. The pharmacokinetics of darapladib and its metabolites; and safety and tolerability will be evaluated.
All the subjects will be admitted to the clinic on the evening of Day -1. Subjects may check out of the clinic on Day 2 after all assessments are complete, but must return to the clinic each day (Days 3-8) for dosing and assessments. Subjects will be admitted to the clinic again on the evening of Day 9. After the last dose of the study drug, there will be a follow-up period which will include 2 visits (Day 20-24 and Day 38-52). The total study duration for each subject including the screening, treatment and follow-up periods will be approximately 11 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Renal Impaired Group | Experimental | Drug: Darapladib 160 mgSubjects with renal impairment received darapladip 160 mg daily for 10 consecutive days. |
| Healthy Control Group | Experimental | Drug: Darapladib 160 mgHealthy volunteers matching with renal impairment subjects for gender, age and BMI; received darapladip 160 mg daily for 10 consecutive days. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- A male or female is eligible to enter and participate in this study if he/she is: A healthy subject with normal renal function: Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with clinical abnormalities or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures; Estimated Creatinine clearance ≥ 90mL/min calculated by Cockcroft-Gault equation using serum creatinine OR A renally impaired subject - To be classified as renally impaired, subjects must have: An estimated Glomerular Filtration Rate (eGFR) of <30 ml/min /1.73 m2 using the four variable Modification of Diet in Renal Disease (MDRD) equation.
- Age between 18 and 75 years inclusive, at the time of signing the informed consent.
- A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140pmol/L) is confirmatory]; Child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the final follow-up visit (35 ± 7 days after last dose of investigational product)
- Body mass index (BMI) within the range of 19.0-38.0 kg/m2 (inclusive)
- Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Key exclusion criteria (39 listed)
- Healthy Subjects
- A positive pre-study drug/alcohol screen.
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody or positive Hepatitis A IGM antibody result within 3 months of screening.
- A positive test for HIV antibody.
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones
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 |
|---|---|---|
| Darapladib 160 mgSubjects in each group received one tablet orally of Darapladib 160 mg daily for 10 consecutive days. Tablets were taken with food, swallowed whole, not chewed. | Drug | Healthy Control Group, Renal Impaired Group |
Primary outcome
AUC (0-τ) for darapladib and as data permit for metabolites M4, M3, and M10
Time frame: On scheduled intervals on Day 10
The PK parameter area under the concentration-time curve over the dosing interval (AUC (0-τ)) will be derived from the plasma concentration-time data.
Cmax for darapladib and as data permit for metabolite s M4, M3, and M10
Time frame: On scheduled intervals on Day 10
The PK parameter maximum observed concentration (Cmax) will be derived from the plasma concentration-time data.
6 secondary outcomes
Spontaneous AE reporting
Time frame: 45days
Clinical laboratory test measurements
Time frame: Day-1, Day 11 and post treatment
Vital signs measurements
Time frame: Day-1, Day1, Day5, Day 11 and post treatment
Nursing/physician observation
Time frame: 20 days
Free fraction (% unbound) of darapladib and its metabolites M3, M4, and M10 (as data permit)
Time frame: On scheduled intervals on Day 10
Tmax and t1/2 of darapladib and its metabolites M3, M4, M3, and M10 (as data permit)
Time frame: On scheduled intervals on Day 10
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 26 Jul 2017.
- Results for study 115676 can be found on the GSK Clinical Study Register.Link provided by the sponsor.
- Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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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.
GSK Clinical Trials study director
GlaxoSmithKline
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Darapladib 160 mg in people with Atherosclerosis, run by GlaxoSmithKline at 2 sites in United States.
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 6 inclusion and 39 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 26 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. 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?
AUC (0-τ) for darapladib and as data permit for metabolites M4, M3, and M10 (time frame: On scheduled intervals on Day 10). The study lists 2 primary outcomes in all. 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 26 Jul 2017.