Drug-induced QT ProlongationPhase 1NCT02308748
Ability of Late Sodium or Calcium Current Block to Balance the ECG Effects of Potassium Current Block
A Phase 1 study testing Dofetilide, Mexiletine and Lidocaine in people with Drug-induced QT Prolongation and Pharmacokinetics, run by Food and Drug Administration (FDA).
Trial summary
The primary objective of this research study is to test the hypothesis that late sodium current blocking drugs (mexiletine or lidocaine) can attenuate the effect of hERG potassium channel blocking drugs (dofetilide) on ventricular repolarization (QTc) by shortening early repolarization (J-Tpeakc). Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug-induced QT Prolongation, Pharmacokinetics, Pharmacodynamics
- What is being tested?
- Dofetilide, Mexiletine and Lidocaine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- No sites listed yet
- Study dates
- May 2014to Jun 2014
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Subject is a healthy man or woman, 18 to 35 years of age, inclusive, who weighs at least 50 kg (110 pounds), no more than 85 kg (197 pounds) and has a body mass index of 18 to 27 kg/m2, inclusive, at Screening.
- Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead ECG results, and physical examination findings at Screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
- Male or female subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from Screening until 30 days after the last dose of study drug.
Who cannot join
- 1. Subject has a 12 lead safety ECG result at Screening or Check in of Period 1 with evidence of any of the following abnormalities:
- QT corrected interval (QTc) using Fridericia correction (QTcF) >430 milliseconds (ms)
- PR interval >220 ms or <120 ms
- QRS duration >110 ms
- Second- or third-degree atrioventricular block
- Complete left or right bundle branch block or incomplete right bundle branch block
Show all 21Show fewer
- Heart rate <50 or >90 beats per minute
- Pathological Q-waves (defined as Q wave >40 ms)
- Ventricular pre-excitation
- 2. Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.
- 3. Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsades de pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will also be excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative due to cardiac causes at a young age) or Brugada syndrome.
- 4. Subject has a history or current evidence of any clinically significant (as determined by the investigator) cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic, psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy (excluding nonmelanoma skin cancer). The investigator may allow exceptions to these criteria (e.g., stable mild joint disease [that will not interfere with or influence the activities required by the protocol, in the opinion of the investigator], cholecystectomy, childhood asthma) following discussion with the medical monitor.
- 5. Subject has a history of thoracic surgery.
- 6. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).
- 7. Subject has a skin condition likely to compromise ECG electrode placement.
- 8. Subject is a female with breast implants.
- 9. Subject's laboratory test results at Screening or Check in of Period 1 are outside the reference ranges provided by the clinical laboratory and considered clinically significant (as determined and documented by the investigator or designee).
- 10. Subject's laboratory test results at Screening or Check in of Period 1 indicate hypokalemia, hypocalcemia, or hypomagnesemia according to lower limits of the reference ranges provided by the clinical laboratory.
- 11. Subject's laboratory test results at Screening or Check in of Period 1 are >2 × the upper limit of normal (ULN) for alanine aminotransferase or aspartate aminotransferase, >1.5 × ULN for bilirubin, or >1.5 × ULN for creatinine.
- 12. Subject has a positive test result at Screening for human immunodeficiency virus, hepatitis C antibodies, or hepatitis B surface antigen.
- 13. Subject has a mean systolic blood pressure <90 or >140 mmHg or a mean diastolic blood pressure <50 or >90 mmHg at either Screening or Check in of Period 1.
About this study
Official title: Five Period Crossover Study of the Ability of Late Sodium or Calcium Current Block (Mexiletine, Lidocaine, or Diltiazem) to Balance the Electrocardiographic Effects of hERG Potassium Current Block (Dofetilide or Moxifloxacin)
The primary objective of this research study is to test the hypothesis that late sodium current blocking drugs (mexiletine or lidocaine) can attenuate the effect of hERG potassium channel blocking drugs (dofetilide) on ventricular repolarization (QTc) by shortening early repolarization (J-Tpeakc). The secondary object is to assess the ability of calcium channel block (diltiazem) to reduce the QTc prolongation associated with hERG block (moxifloxacin).
Read the detailed description
This is a randomized, double-blind, 5-period crossover study in healthy male and female subjects, 18 to 35 years of age, to compare the electrophysiological response of hERG potassium channel blocking drugs with and without the addition of late sodium or calcium channel blocking drugs. The 5 treatment periods are 1) dofetilide alone, 2) mexiletine with and without dofetilide, 3) lidocaine with and without dofetilide, 4) moxifloxacin with and without diltiazem and 5) placebo. During each treatment period, 12 blood samples for pharmacokinetic measurements are obtained with matched 12-lead ECG recordings.
- Being tested
- Dofetilide, Mexiletine, Lidocaine, Moxifloxacin, Diltiazem
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DofetilideDrug
Also called Tikosyn
- 8 am: Placebo
- 12 pm (noon): 250 µg
- 5:30 pm: 250 µg
MexiletineDrug
Also called Mexitil
- 8 am: weight x 4 mg/kg
- 12 pm (noon): Same as at 8 am
- 5:30 pm: Same as at 8 am
LidocaineDrug
Also called Lidocaine hydrochloride
- 9 am : 30 µg/min per kg (loading) for 60 minutes and 10 µg/min per kg (maintenance) for 30 minutes
- 2 pm: 55 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes
- 7:30 pm: 52 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes
MoxifloxacinDrug
Also called Avelox
- 9 am: 5.63 mg/h per kg (loading) for 1 hour and 0.26 mg/h per kg (maintenance for 30 minutes)
- 2 pm: 6.14 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes)
- 7:30 pm: 2.23 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes)
DiltiazemDrug
Also called Diltiazem hydrochloride
- 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes
PlaceboDrug
Also called #2 Gelcaps or IV saline
Placebo (#2 Gelcap or IV saline)
| Study group | Role | What they receive |
|---|---|---|
| Dofetilide | Active comparator | Dofetilide alone arm Receives: Drug: Dofetilide |
| Dofetilide + Mexiletine | Active comparator | Dofetilide combined with mexiletine Receives: Drug: Dofetilide; Drug: Mexiletine |
| Dofetilide + Lidocaine | Active comparator | Dofetilide combined with lidocaine Receives: Drug: Dofetilide; Drug: Lidocaine |
| Moxifloxacin + Diltiazem | Active comparator | Moxifloxacin with and without diltiazem. Receives: Drug: Moxifloxacin; Drug: Diltiazem |
| Placebo | Placebo comparator | Placebo (#2 gelcap and intravenous saline) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Placebo Corrected Change From Baseline QTc and J-Tpeakc Intervals on the ECG Measured in Milliseconds When Dofetilide is Administered With Mexiletine or Lidocaine Compared to When Dofetilide is Administered Alone at Evening Dose on Treatment Day
After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day.
Measured: 5 weeks
Secondary outcomes (1)
Change in Placebo Corrected Change From Baseline QTc Interval on the ECG Measured in Milliseconds When Moxifloxacin is Administered With Diltiazem at the Evening Dose Compared to When Moxifloxacin is Administered Alone at Afternoon Dose on Treatment Day.
Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).
Measured: 5 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2014 (estimated)
- Study startMay 2014
- Primary completionJun 2014
- Study completionJun 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Drug-induced QT ProlongationStudies of the same condition, open and under way.
- 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
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Food and Drug Administration (FDA)
- Sponsor type
- US federal agency
- Collaborators
- Spaulding Clinical Research LLC
- Responsible party
- Sponsor
- Investigators
- Carlos Sanabria, MD, Principal investigator, Spaulding Clinical
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02308748
- Sponsor's protocol ID
- 14-022D
- Other IDs
- SCR-003
- Status last verified
- Jun 2016
- First submitted
- 6 Nov 2014
- Last updated
- 8 Jun 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Johannesen L, Vicente J, Mason JW, Erato C, Sanabria C, Waite-Labott K, Hong M, Lin J, Guo P, Mutlib A, Wang J, Crumb WJ, Blinova K, Chan D, Stohlman J, Florian J, Ugander M, Stockbridge N, Strauss DG. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial. Clin Pharmacol Ther. 2016 Feb;99(2):214-23. doi: 10.1002/cpt.205. Epub 2015 Nov 28.
PubMed 26259627Vicente J, Johannesen L, Hosseini M, Mason JW, Sager PT, Pueyo E, Strauss DG. Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block. PLoS One. 2016 Dec 30;11(12):e0163619. doi: 10.1371/journal.pone.0163619. eCollection 2016.
PubMed 28036334Johannesen L, Vicente J, Hosseini M, Strauss DG. Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk. PLoS One. 2016 Dec 30;11(12):e0166925. doi: 10.1371/journal.pone.0166925. eCollection 2016.
PubMed 28036330
Study at a glance
From the registry record, last updated by the sponsor on 8 Jun 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Five Period Crossover Study of the Ability of Late Sodium or Calcium Current Block (Mexiletine, Lidocaine, or Diltiazem) to Balance the Electrocardiographic Effects of hERG Potassium Current Block (Dofetilide or Moxifloxacin)
- ClinicalTrials.gov ID
- NCT02308748
- Acronym / sponsor ID
- 14-022D
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Food and Drug Administration (FDA)US federal agency
- Collaborators
- Spaulding Clinical Research LLC
- Study start
- May 2014
- Primary completion
- Jun 2014 (actual)
- Study completion
- Jun 2014 (actual)
- First posted
- 4 Dec 2014 (estimated)
- Results
- Posted 8 Jun 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of this research study is to test the hypothesis that late sodium current blocking drugs (mexiletine or lidocaine) can attenuate the effect of hERG potassium channel blocking drugs (dofetilide) on ventricular repolarization (QTc) by shortening early repolarization (J-Tpeakc). The secondary object is to assess the ability of calcium channel block (diltiazem) to reduce the QTc prolongation associated with hERG block (moxifloxacin).
Detailed description
This is a randomized, double-blind, 5-period crossover study in healthy male and female subjects, 18 to 35 years of age, to compare the electrophysiological response of hERG potassium channel blocking drugs with and without the addition of late sodium or calcium channel blocking drugs. The 5 treatment periods are 1) dofetilide alone, 2) mexiletine with and without dofetilide, 3) lidocaine with and without dofetilide, 4) moxifloxacin with and without diltiazem and 5) placebo. During each treatment period, 12 blood samples for pharmacokinetic measurements are obtained with matched 12-lead ECG recordings.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Dofetilide | Active comparator | Drug: DofetilideDofetilide alone arm |
| Dofetilide + Mexiletine | Active comparator | Drug: Dofetilide, Drug: MexiletineDofetilide combined with mexiletine |
| Dofetilide + Lidocaine | Active comparator | Drug: Dofetilide, Drug: LidocaineDofetilide combined with lidocaine |
| Moxifloxacin + Diltiazem | Active comparator | Drug: Moxifloxacin, Drug: DiltiazemMoxifloxacin with and without diltiazem. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo (#2 gelcap and intravenous saline) |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Subject is a healthy man or woman, 18 to 35 years of age, inclusive, who weighs at least 50 kg (110 pounds), no more than 85 kg (197 pounds) and has a body mass index of 18 to 27 kg/m2, inclusive, at Screening.
- Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead ECG results, and physical examination findings at Screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
- Male or female subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from Screening until 30 days after the last dose of study drug.
Key exclusion criteria (21 listed)
- 1. Subject has a 12 lead safety ECG result at Screening or Check in of Period 1 with evidence of any of the following abnormalities:
- 2. Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.
- 3. Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsades de pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will also be excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative due to cardiac causes at a young age) or Brugada syndrome.
- 4. Subject has a history or current evidence of any clinically significant (as determined by the investigator) cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic, psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy (excluding nonmelanoma skin cancer). The investigator may allow exceptions to these criteria (e.g., stable mild joint disease [that will not interfere with or influence the activities required by the protocol, in the opinion of the investigator], cholecystectomy, childhood asthma) following discussion with the medical monitor.
- 5. Subject has a history of thoracic surgery.
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 |
|---|---|---|
| DofetilideAlso: Tikosyn* 8 am: Placebo * 12 pm (noon): 250 µg * 5:30 pm: 250 µg | Drug | Dofetilide, Dofetilide + Lidocaine, Dofetilide + Mexiletine |
| MexiletineAlso: Mexitil* 8 am: weight x 4 mg/kg * 12 pm (noon): Same as at 8 am * 5:30 pm: Same as at 8 am | Drug | Dofetilide + Mexiletine |
| LidocaineAlso: Lidocaine hydrochloride* 9 am : 30 µg/min per kg (loading) for 60 minutes and 10 µg/min per kg (maintenance) for 30 minutes * 2 pm: 55 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes * 7:30 pm: 52 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes | Drug | Dofetilide + Lidocaine |
| MoxifloxacinAlso: Avelox* 9 am: 5.63 mg/h per kg (loading) for 1 hour and 0.26 mg/h per kg (maintenance for 30 minutes) * 2 pm: 6.14 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes) * 7:30 pm: 2.23 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes) | Drug | Moxifloxacin + Diltiazem |
| DiltiazemAlso: Diltiazem hydrochloride• 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes | Drug | Moxifloxacin + Diltiazem |
| PlaceboAlso: #2 Gelcaps or IV salinePlacebo (#2 Gelcap or IV saline) | Drug | Placebo |
Primary outcome
Change in Placebo Corrected Change From Baseline QTc and J-Tpeakc Intervals on the ECG Measured in Milliseconds When Dofetilide is Administered With Mexiletine or Lidocaine Compared to When Dofetilide is Administered Alone at Evening Dose on Treatment Day
Time frame: 5 weeks
After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day.
1 secondary outcome
Change in Placebo Corrected Change From Baseline QTc Interval on the ECG Measured in Milliseconds When Moxifloxacin is Administered With Diltiazem at the Evening Dose Compared to When Moxifloxacin is Administered Alone at Afternoon Dose on Treatment Day.
Time frame: 5 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jun 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 26259627Johannesen L, Vicente J, Mason JW, Erato C, Sanabria C, Waite-Labott K, Hong M, Lin J, Guo P, Mutlib A, Wang J, Crumb WJ, Blinova K, Chan D, Stohlman J, Florian J, Ugander M, Stockbridge N, Strauss DG. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial. Clin Pharmacol Ther. 2016 Feb;99(2):214-23. doi: 10.1002/cpt.205. Epub 2015 Nov 28.
- Derived from this study: PubMed 28036334Vicente J, Johannesen L, Hosseini M, Mason JW, Sager PT, Pueyo E, Strauss DG. Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block. PLoS One. 2016 Dec 30;11(12):e0163619. doi: 10.1371/journal.pone.0163619. eCollection 2016.
- Derived from this study: PubMed 28036330Johannesen L, Vicente J, Hosseini M, Strauss DG. Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk. PLoS One. 2016 Dec 30;11(12):e0166925. doi: 10.1371/journal.pone.0166925. eCollection 2016.
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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.
Carlos Sanabria, MD principal investigator
Spaulding Clinical
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Dofetilide, Mexiletine and Lidocaine in people with Drug-induced QT Prolongation and Pharmacokinetics, run by Food and Drug Administration (FDA).
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 3 inclusion and 21 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 8 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. 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?
Yes. Results are posted in the registry (first posted 8 Jun 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Change in Placebo Corrected Change From Baseline QTc and J-Tpeakc Intervals on the ECG Measured in Milliseconds When Dofetilide is Administered With Mexiletine or Lidocaine Compared to When Dofetilide is Administered Alone at Evening Dose on Treatment Day (time frame: 5 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02308748, which also lists 3 linked publications.
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 8 Jun 2016.