Drug-induced QT ProlongationPhase 1NCT03070470
CiPA Phase 1 ECG Biomarker Validation Study
A Phase 1 study testing Ranolazine, Verapamil and Lopinavir / Ritonavir in people with Drug-induced QT Prolongation and Pharmacokinetics, run by Food and Drug Administration (FDA) at 1 site in United States.
Trial summary
This study will assess whether exposure response analysis of the electrocardiographic QTc and J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that drugs that predominantly block the potassium channel encoded by the human ether-à-go-go-related gene (hERG) with approximately equipotent… Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug-induced QT Prolongation, Pharmacokinetics, Pharmacodynamics
- What is being tested?
- Ranolazine, Verapamil and Lopinavir / Ritonavir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Mar 2017to 26 Jun 2017
- 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 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Subject signs an institutional review board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] authorization) before any study related procedures are performed.
- Subject is a healthy man or woman, 18 to 50 years of age, inclusive, who weighs at least 50 kg (110 pounds) and has a body mass index of 18 to 30 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).
- Female subjects will be at least 2 years postmenopausal, surgically sterile, or practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique).
- Female subjects must not be pregnant or lactating before enrollment in the study.
- 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.
- Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.
Who cannot join
- Subject has a safety 12 lead ECG result at Screening or Check in with evidence of any of the following abnormalities:
- QTc using Fridericia correction (QTcF) >430 msec
- PR interval >220 msec or <120 msec
- QRS duration >110 msec
- Second- or third-degree atrioventricular block
- Complete left or right bundle branch block or incomplete right bundle branch block
Show all 32Show fewer
- Heart rate <50 or >90 beats per minute
- Pathological Q-waves (defined as Q wave >40 msec)
- Ventricular pre-excitation
- Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.
- Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsade 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.
- 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., cholecystectomy, childhood asthma) following discussion with the medical monitor.
- Subject has a history of thoracic surgery.
- Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).
- Subject has a skin condition likely to compromise ECG electrode placement.
- Subject is a female with breast implants.
- Subject's laboratory test results at Screening or Check in are outside the reference ranges provided by the clinical laboratory and considered clinically significant (as determined and documented by the investigator or designee).
- Subject's laboratory test results at Screening or Check in indicate hypokalemia, hypocalcemia, or hypomagnesemia according to lower limits of the reference ranges provided by the clinical laboratory.
- Subject's laboratory test results at Screening or Check in 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.
- Subject has a positive test result at Screening for human immunodeficiency virus I or II antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
- Subject has a mean systolic blood pressure <100 or >140 mmHg or a mean diastolic blood pressure <50 or >90 mmHg at either Screening or Check in. Blood pressure will be measured in triplicate after the subject has been resting in a supine position for a minimum of 5 minutes.
- Subject has a known hypersensitivity to any of the study drugs or related compounds.
- Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 48 hours before dosing or anticipates an inability to abstain from these products throughout the duration of the study.
- Subject has used nicotine containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks before Screening (self reported).
- Subject is unable to tolerate a controlled, quiet, study conduct environment, including avoidance of music, television, movies, games, and activities that may cause excitement, emotional tension, or arousal during the prespecified time points (e.g., before and during ECG extraction windows).
- Subject is unwilling to comply with study rules, including the study-specific diet, attempting to void at specified times (e.g., before ECG extraction windows), remaining quiet, awake, undistracted, motionless, and supine during specified times, and avoiding vigorous exercise as directed.
- Subject has a history of consuming more than 14 units of alcoholic beverages per week within 6 months before Screening, has a history of alcoholism or drug/chemical/substance abuse within 2 years before Screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits/hard liquor), or has a positive test result for alcohol or drugs of abuse at Screening or Check in.
- Subject has used any prescription or nonprescription drugs (including aspirin or nonsteroidal anti inflammatory drugs [NSAIDs] and excluding oral contraceptives and acetaminophen) within 14 days or 5 half lives (whichever is longer), or complementary and alternative medicines within 28 days before the first dose of study drug.
- Subject is currently participating in another clinical study of an investigational drug or has been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of the compound.
- Subject has had any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days, or donated plasma within 7 days before Check in.
- Subject has any other condition that precludes his or her participation in the study (as determined by the investigator).
- Subject is unwilling to have genetic analysis performed or a blood sample collected for isolating peripheral blood mononuclear cells (PBMCs).
Trial locations and contacts
1 site in 1 country.
United States1 site
Spaulding Clinical Research
West Bend, Wisconsin, 53095
About this study
Official title: Comprehensive in Vitro Proarrhythmia Assay (CiPA) Clinical Phase 1 ECG Biomarker Validation Study (CiPA Phase 1 ECG Biomarker Study)
This study will assess whether exposure response analysis of the electrocardiographic QTc and J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that drugs that predominantly block the potassium channel encoded by the human ether-à-go-go-related gene (hERG) with approximately equipotent late sodium and/or calcium block ("balanced ion channel" drugs) do not cause J-Tpeakc prolongation and that drugs that predominantly block hERG without late sodium or L-type calcium current block ("predominant hERG" drugs) cause QTc prolongation.
Read the detailed description
This study will assess whether exposure response analysis of the electrocardiographic QTc and J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that "balanced ion channel" drugs do not cause J-Tpeakc prolongation and that "predominant hERG" drugs cause QTc prolongation. This clinical study consists of 2 parts: a 50-subject parallel part (Part 1) and a 10-subject crossover part (Part 2). Up to 74 healthy subjects will be enrolled (including 14 potential replacement subjects).
Part 1 will be a double-blind, randomized, placebo-controlled, 1 period parallel design to assess the effect of 4 marketed drugs and 1 placebo on the QTc and J-Tpeakc intervals in 50 healthy subjects. A parallel design similar to a single or multiple ascending dose (SAD/MAD) Phase 1 study will be used that will result in each study drug being administered to 10 subjects, and placebo to 10 subjects, in 1 period of 3 consecutive days to achieve low and high drug exposure.
Part 2 will be a double-blind, randomized, 2-period crossover design to assess the effect of hERG block (dofetilide) versus calcium block (diltiazem) on the QTc and J-Tpeakc intervals in 10 healthy subjects on Days 1, 2, and 3 (Period 1) and Days 8, 9, and 10 (Period 2).
- Being tested
- Ranolazine, Verapamil, Lopinavir / Ritonavir, Chloroquine, Placebo
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RanolazineDrug
Ranolazine 1500 mg orally two times per day for 2.5 days
VerapamilDrug
Verapamil 120 mg immediate release (IR) morning and afternoon doses on Days 1 and 2, 240 mg extended release (ER) evening dose on Days 1 and 2, and 120 mg IR morning dose on Day 3 (all oral doses)
Lopinavir / RitonavirDrug
Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days
ChloroquineDrug
Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses)
PlaceboDrug
Placebo (administered orally)
Dofetilide and DiltiazemDrug
In one period subjects receive Dofetilide 0.125 mg on Day 1, 0.375 mg on Day 3.
In a second period (randomized cross-over) subject receive Diltiazem 120 mg IR morning dose on Day 8, 240 mg ER evening dose on Days 8 and 9, and 120 mg IR on Day 10 with coadministration of 0.25 mg dofetilide on Day 10.
| Study group | Role | What they receive |
|---|---|---|
| Ranolazine | Active comparator | Ranolazine 1500 mg two times per day for 2.5 days Receives: Drug: Ranolazine |
| Verapamil | Active comparator | Verapamil 120 mg immediate release (IR) morning and afternoon doses on Days 1 and 2, 240 mg extended release (ER) evening dose on Days 1 and 2, and 120 mg IR morning dose on Day 3 Receives: Drug: Verapamil |
| Lopinavir / Ritonavir | Active comparator | Lopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days Receives: Drug: Lopinavir / Ritonavir |
| Chloroquine | Active comparator | Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 Receives: Drug: Chloroquine |
| Placebo | Placebo comparator | Placebo capsules Receives: Drug: Placebo |
| Dofetilide and Diltiazem | Active comparator | In one period subjects receive Dofetilide 0.125 mg on Day 1, 0.375 mg on Day 3.
In a second period (randomized cross-over) subject receive Diltiazem 120 mg IR morning dose on Day 8, 240 mg ER evening dose on Days 8 and 9, and 120 mg IR on Day 10 with coadministration of 0.25 mg dofetilide on Day 10. Receives: Drug: Dofetilide and Diltiazem |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline J-Tpeakc With "Balanced Ion Channel" Drugs (Ranolazine, Verapamil, Lopinavir / Ritonavir)
The primary outcome measure for the "balanced ion channel" drugs (ranolazine, verapamil, lopinavir / ritonavir) is for the upper bound of the 2-sided 90% confidence interval (CI) to be <10 msec for the projected placebo-corrected change from baseline J-Tpeakc effect at the peak plasma level on Day 3 using a linear mixed-effects exposure response model. Placebo drug concentration was set to 0 (see SAP).
Measured: 3 days
Change From Baseline QTc With "Predominant hERG" Blocking Drug (Chloroquine)
The primary outcome measure for the "predominant hERG" drug (chloroquine) is for the upper bound of the 2-sided 90% CI to be ≥10 msec for the projected placebo-corrected change from baseline QTc effect at the peak plasma level on Day 1 using a linear mixed-effects exposure response model
Measured: 3 days
QTc Shortening From Calcium Block (Diltiazem) in the Presence of hERG Block (Dofetilide)
- It will be assessed whether the projected QTc effect of dofetilide alone is significantly greater (i.e., p<0.05) than the projected QTc effect of the combination of dofetilide + diltiazem. This will be assessed at the dofetilide peak plasma level on Day 3 (computed from the combination of dofetilide + diltiazem) on the pooled dofetilide alone, diltiazem alone, and dofetilide + diltiazem data using a linear mixed effects model.
- Subsequently, and if the test is significant for QTc, the same test will be performed to assess calcium block (diltiazem) effects on J-Tpeakc.
Measured: 3 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Mar 2017
- Study start14 Mar 2017
- Primary completion26 Jun 2017
- Study completion26 Jun 2017
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
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This clinical study consists of 2 parts: * 50 subjects in Part 1 will be randomized to receive one of four drugs (ranolazine, verapamil, lopinavir / ritonavir, chloroquine) or placebo over 3 days. * 10 subjects in Part 2 will be randomized to receive one of two treatment sequences (1. dofetilide or 2. diltiazem combined with dofetilide) over 3 days, then after washout, the subjects will receive the other treatment sequence over 3 days. Thus, Part 2 will have a cross-over component. A maximum of 14 additional replacement subjects may be enrolled.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 60 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 Research LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03070470
- Sponsor's protocol ID
- 16-086D
- Other IDs
- SCR-004
- Status last verified
- Jan 2020
- First submitted
- 27 Feb 2017
- Last updated
- 18 Jan 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Study protocol and statistical analysis plan released as supplementary materials together with study design and rationale manuscript. ECG analysis plan published together with an update of the CiPA initiative. Annotated ECG waveforms, pharmacokinetic, and other subject level clinical data released as ECGCIPA database in PhysioNet. Clinical study report and analytic code released as supporting information (i.e., study results report) of study results manuscript. See references section.
Publications
Vicente J, Zusterzeel R, Johannesen L, Mason J, Sager P, Patel V, Matta MK, Li Z, Liu J, Garnett C, Stockbridge N, Zineh I, Strauss DG. Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study. Clin Pharmacol Ther. 2018 Jan;103(1):54-66. doi: 10.1002/cpt.896. Epub 2017 Nov 16.
PubMed 28986934Vicente J. Update on the ECG component of the CiPA initiative. J Electrocardiol. 2018 Nov-Dec;51(6S):S98-S102. doi: 10.1016/j.jelectrocard.2018.08.003. Epub 2018 Aug 7.
PubMed 30121123Vicente J, Zusterzeel R, Johannesen L, Ochoa-Jimenez R, Mason JW, Sanabria C, Kemp S, Sager PT, Patel V, Matta MK, Liu J, Florian J, Garnett C, Stockbridge N, Strauss DG. Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study. Clin Pharmacol Ther. 2019 Apr;105(4):943-953. doi: 10.1002/cpt.1303. Epub 2019 Jan 18.
PubMed 30447156
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comprehensive in Vitro Proarrhythmia Assay (CiPA) Clinical Phase 1 ECG Biomarker Validation Study (CiPA Phase 1 ECG Biomarker Study)
- ClinicalTrials.gov ID
- NCT03070470
- Acronym / sponsor ID
- 16-086D
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Food and Drug Administration (FDA)US federal agency
- Collaborators
- Spaulding Clinical Research LLC
- Study start
- 14 Mar 2017 (actual)
- Primary completion
- 26 Jun 2017 (actual)
- Study completion
- 26 Jun 2017 (actual)
- First posted
- 3 Mar 2017 (actual)
- Results
- Posted 18 Jan 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will assess whether exposure response analysis of the electrocardiographic QTc and J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that drugs that predominantly block the potassium channel encoded by the human ether-à-go-go-related gene (hERG) with approximately equipotent late sodium and/or calcium block ("balanced ion channel" drugs) do not cause J-Tpeakc prolongation and that drugs that predominantly block hERG without late sodium or L-type calcium current block ("predominant hERG" drugs) cause QTc prolongation.
Detailed description
This study will assess whether exposure response analysis of the electrocardiographic QTc and J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that "balanced ion channel" drugs do not cause J-Tpeakc prolongation and that "predominant hERG" drugs cause QTc prolongation. This clinical study consists of 2 parts: a 50-subject parallel part (Part 1) and a 10-subject crossover part (Part 2). Up to 74 healthy subjects will be enrolled (including 14 potential replacement subjects).
Part 1 will be a double-blind, randomized, placebo-controlled, 1 period parallel design to assess the effect of 4 marketed drugs and 1 placebo on the QTc and J-Tpeakc intervals in 50 healthy subjects. A parallel design similar to a single or multiple ascending dose (SAD/MAD) Phase 1 study will be used that will result in each study drug being administered to 10 subjects, and placebo to 10 subjects, in 1 period of 3 consecutive days to achieve low and high drug exposure.
Part 2 will be a double-blind, randomized, 2-period crossover design to assess the effect of hERG block (dofetilide) versus calcium block (diltiazem) on the QTc and J-Tpeakc intervals in 10 healthy subjects on Days 1, 2, and 3 (Period 1) and Days 8, 9, and 10 (Period 2).
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 6
- Model description
- This clinical study consists of 2 parts: * 50 subjects in Part 1 will be randomized to receive one of four drugs (ranolazine, verapamil, lopinavir / ritonavir, chloroquine) or placebo over 3 days. * 10 subjects in Part 2 will be randomized to receive one of two treatment sequences (1. dofetilide or 2. diltiazem combined with dofetilide) over 3 days, then after washout, the subjects will receive the other treatment sequence over 3 days. Thus, Part 2 will have a cross-over component. A maximum of 14 additional replacement subjects may be enrolled.
| Arm | Type | Receives |
|---|---|---|
| Ranolazine | Active comparator | Drug: RanolazineRanolazine 1500 mg two times per day for 2.5 days |
| Verapamil | Active comparator | Drug: VerapamilVerapamil 120 mg immediate release (IR) morning and afternoon doses on Days 1 and 2, 240 mg extended release (ER) evening dose on Days 1 and 2, and 120 mg IR morning dose on Day 3 |
| Lopinavir / Ritonavir | Active comparator | Drug: Lopinavir / RitonavirLopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days |
| Chloroquine | Active comparator | Drug: ChloroquineChloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo capsules |
| Dofetilide and Diltiazem | Active comparator | Drug: Dofetilide and DiltiazemIn one period subjects receive Dofetilide 0.125 mg on Day 1, 0.375 mg on Day 3. In a second period (randomized cross-over) subject receive Diltiazem 120 mg IR morning dose on Day 8, 240 mg ER evening dose on Days 8 and 9, and 120 mg IR on Day 10 with coadministration of 0.25 mg dofetilide on Day 10. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Subject signs an institutional review board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] authorization) before any study related procedures are performed.
- Subject is a healthy man or woman, 18 to 50 years of age, inclusive, who weighs at least 50 kg (110 pounds) and has a body mass index of 18 to 30 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).
- Female subjects will be at least 2 years postmenopausal, surgically sterile, or practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique).
- Female subjects must not be pregnant or lactating before enrollment in the study.
Key exclusion criteria (32 listed)
- Subject has a safety 12 lead ECG result at Screening or Check in with evidence of any of the following abnormalities:
- Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.
- Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsade 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.
- 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., cholecystectomy, childhood asthma) following discussion with the medical monitor.
- 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 |
|---|---|---|
| RanolazineRanolazine 1500 mg orally two times per day for 2.5 days | Drug | Ranolazine |
| VerapamilVerapamil 120 mg immediate release (IR) morning and afternoon doses on Days 1 and 2, 240 mg extended release (ER) evening dose on Days 1 and 2, and 120 mg IR morning dose on Day 3 (all oral doses) | Drug | Verapamil |
| Lopinavir / RitonavirLopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days | Drug | Lopinavir / Ritonavir |
| ChloroquineChloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses) | Drug | Chloroquine |
| PlaceboPlacebo (administered orally) | Drug | Placebo |
| Dofetilide and DiltiazemIn one period subjects receive Dofetilide 0.125 mg on Day 1, 0.375 mg on Day 3. In a second period (randomized cross-over) subject receive Diltiazem 120 mg IR morning dose on Day 8, 240 mg ER evening dose on Days 8 and 9, and 120 mg IR on Day 10 with coadministration of 0.25 mg dofetilide on Day 10. | Drug | Dofetilide and Diltiazem |
Primary outcome
Change From Baseline J-Tpeakc With "Balanced Ion Channel" Drugs (Ranolazine, Verapamil, Lopinavir / Ritonavir)
Time frame: 3 days
The primary outcome measure for the "balanced ion channel" drugs (ranolazine, verapamil, lopinavir / ritonavir) is for the upper bound of the 2-sided 90% confidence interval (CI) to be <10 msec for the projected placebo-corrected change from baseline J-Tpeakc effect at the peak plasma level on Day 3 using a linear mixed-effects exposure response model. Placebo drug concentration was set to 0 (see SAP).
Change From Baseline QTc With "Predominant hERG" Blocking Drug (Chloroquine)
Time frame: 3 days
The primary outcome measure for the "predominant hERG" drug (chloroquine) is for the upper bound of the 2-sided 90% CI to be ≥10 msec for the projected placebo-corrected change from baseline QTc effect at the peak plasma level on Day 1 using a linear mixed-effects exposure response model
QTc Shortening From Calcium Block (Diltiazem) in the Presence of hERG Block (Dofetilide)
Time frame: 3 days
* It will be assessed whether the projected QTc effect of dofetilide alone is significantly greater (i.e., p<0.05) than the projected QTc effect of the combination of dofetilide + diltiazem. This will be assessed at the dofetilide peak plasma level on Day 3 (computed from the combination of dofetilide + diltiazem) on the pooled dofetilide alone, diltiazem alone, and dofetilide + diltiazem data using a linear mixed effects model. * Subsequently, and if the test is significant for QTc, the same test will be performed to assess calcium block (diltiazem) effects on J-Tpeakc.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 28986934Vicente J, Zusterzeel R, Johannesen L, Mason J, Sager P, Patel V, Matta MK, Li Z, Liu J, Garnett C, Stockbridge N, Zineh I, Strauss DG. Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study. Clin Pharmacol Ther. 2018 Jan;103(1):54-66. doi: 10.1002/cpt.896. Epub 2017 Nov 16.
- Background: PubMed 30121123Vicente J. Update on the ECG component of the CiPA initiative. J Electrocardiol. 2018 Nov-Dec;51(6S):S98-S102. doi: 10.1016/j.jelectrocard.2018.08.003. Epub 2018 Aug 7.
- Results publication: PubMed 30447156Vicente J, Zusterzeel R, Johannesen L, Ochoa-Jimenez R, Mason JW, Sanabria C, Kemp S, Sager PT, Patel V, Matta MK, Liu J, Florian J, Garnett C, Stockbridge N, Strauss DG. Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study. Clin Pharmacol Ther. 2019 Apr;105(4):943-953. doi: 10.1002/cpt.1303. Epub 2019 Jan 18.
- Individual participant dataSharing planned: Yes. Study protocol and statistical analysis plan released as supplementary materials together with study design and rationale manuscript. ECG analysis plan published together with an update of the CiPA initiative. Annotated ECG waveforms, pharmacokinetic, and other subject level clinical data released as ECGCIPA database in PhysioNet. Clinical study report and analytic code released as supporting information (i.e., study results report) of study results manuscript. See references section.
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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 Research LLC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ranolazine, Verapamil and Lopinavir / Ritonavir in people with Drug-induced QT Prolongation and Pharmacokinetics, run by Food and Drug Administration (FDA) at 1 site 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 7 inclusion and 32 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 18 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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. 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 18 Jan 2020). 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 From Baseline J-Tpeakc With "Balanced Ion Channel" Drugs (Ranolazine, Verapamil, Lopinavir / Ritonavir) (time frame: 3 days). The study lists 3 primary outcomes in all. 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 NCT03070470, 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 18 Jan 2020.