Trial Outcomes & Findings for CiPA Phase 1 ECG Biomarker Validation Study (NCT NCT03070470)

Last Updated: 2020-01-18

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

60 participants

Primary outcome timeframe

3 days

Results posted on

2020-01-18

Participant Flow

Participant milestones

Participant milestones
Measure	Ranolazine Ranolazine 1500 mg two times per day for 2.5 days Ranolazine: Ranolazine 1500 mg orally two times per day for 2.5 days	Verapamil 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 Verapamil: 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 / Ritonavir Lopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days Lopinavir / Ritonavir: Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days	Chloroquine Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 Chloroquine: Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses)	Placebo Placebo capsules Placebo: Placebo (administered orally)	Dofetilide and Diltiazem 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. Dofetilide and Diltiazem: 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.
Overall Study STARTED	10	10	10	10	10	10
Overall Study COMPLETED	10	9	10	10	10	8
Overall Study NOT COMPLETED	0	1	0	0	0	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

CiPA Phase 1 ECG Biomarker Validation Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ranolazine n=10 Participants Ranolazine 1500 mg two times per day for 2.5 days Ranolazine: Ranolazine 1500 mg orally two times per day for 2.5 days	Verapamil n=10 Participants 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 Verapamil: 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 / Ritonavir n=10 Participants Lopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days Lopinavir / Ritonavir: Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days	Chloroquine n=10 Participants Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 Chloroquine: Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses)	Placebo n=10 Participants Placebo capsules Placebo: Placebo (administered orally)	Dofetilide and Diltiazem n=10 Participants 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. Dofetilide and Diltiazem: 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.	Total n=60 Participants Total of all reporting groups
Age, Continuous	33.8 years STANDARD_DEVIATION 8.0 • n=93 Participants	28.2 years STANDARD_DEVIATION 7.9 • n=4 Participants	32.6 years STANDARD_DEVIATION 11.1 • n=27 Participants	28.8 years STANDARD_DEVIATION 8.8 • n=483 Participants	33.3 years STANDARD_DEVIATION 9.0 • n=36 Participants	33.4 years STANDARD_DEVIATION 7.2 • n=10 Participants	31.7 years STANDARD_DEVIATION 8.7 • n=115 Participants
Sex: Female, Male Female	2 Participants n=93 Participants	4 Participants n=4 Participants	6 Participants n=27 Participants	3 Participants n=483 Participants	2 Participants n=36 Participants	5 Participants n=10 Participants	22 Participants n=115 Participants
Sex: Female, Male Male	8 Participants n=93 Participants	6 Participants n=4 Participants	4 Participants n=27 Participants	7 Participants n=483 Participants	8 Participants n=36 Participants	5 Participants n=10 Participants	38 Participants n=115 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants	2 Participants n=36 Participants	1 Participants n=10 Participants	4 Participants n=115 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=93 Participants	9 Participants n=4 Participants	10 Participants n=27 Participants	9 Participants n=483 Participants	8 Participants n=36 Participants	9 Participants n=10 Participants	55 Participants n=115 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	1 Participants n=115 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants	1 Participants n=36 Participants	0 Participants n=10 Participants	4 Participants n=115 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Black or African American	6 Participants n=93 Participants	5 Participants n=4 Participants	5 Participants n=27 Participants	7 Participants n=483 Participants	5 Participants n=36 Participants	4 Participants n=10 Participants	32 Participants n=115 Participants
Race (NIH/OMB) White	3 Participants n=93 Participants	4 Participants n=4 Participants	5 Participants n=27 Participants	2 Participants n=483 Participants	4 Participants n=36 Participants	6 Participants n=10 Participants	24 Participants n=115 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Region of Enrollment United States	10 Participants n=93 Participants	10 Participants n=4 Participants	10 Participants n=27 Participants	10 Participants n=483 Participants	10 Participants n=36 Participants	10 Participants n=10 Participants	60 Participants n=115 Participants
Weight	80.3 Kg STANDARD_DEVIATION 11.1 • n=93 Participants	77.1 Kg STANDARD_DEVIATION 10.2 • n=4 Participants	76.2 Kg STANDARD_DEVIATION 6.1 • n=27 Participants	72.4 Kg STANDARD_DEVIATION 11.3 • n=483 Participants	77.5 Kg STANDARD_DEVIATION 15.6 • n=36 Participants	69.5 Kg STANDARD_DEVIATION 9.4 • n=10 Participants	75.5 Kg STANDARD_DEVIATION 11.1 • n=115 Participants
Systolic Blood Pressure	116.6 mmHg STANDARD_DEVIATION 9.5 • n=93 Participants	109.2 mmHg STANDARD_DEVIATION 6.6 • n=4 Participants	119.4 mmHg STANDARD_DEVIATION 10.0 • n=27 Participants	114.8 mmHg STANDARD_DEVIATION 8.1 • n=483 Participants	116.6 mmHg STANDARD_DEVIATION 6.4 • n=36 Participants	113.4 mmHg STANDARD_DEVIATION 8.2 • n=10 Participants	115.0 mmHg STANDARD_DEVIATION 8.5 • n=115 Participants
Diastolic Blood Pressure	66.7 mmHg STANDARD_DEVIATION 8.7 • n=93 Participants	63.4 mmHg STANDARD_DEVIATION 6.9 • n=4 Participants	67.3 mmHg STANDARD_DEVIATION 8.5 • n=27 Participants	66.9 mmHg STANDARD_DEVIATION 5.5 • n=483 Participants	66.7 mmHg STANDARD_DEVIATION 9.0 • n=36 Participants	64.2 mmHg STANDARD_DEVIATION 6.9 • n=10 Participants	65.9 mmHg STANDARD_DEVIATION 7.5 • n=115 Participants
Heart Rate	59.8 BPM STANDARD_DEVIATION 8.9 • n=93 Participants	63.6 BPM STANDARD_DEVIATION 9.8 • n=4 Participants	61.3 BPM STANDARD_DEVIATION 9.3 • n=27 Participants	59.2 BPM STANDARD_DEVIATION 9.5 • n=483 Participants	58.6 BPM STANDARD_DEVIATION 5.6 • n=36 Participants	61.9 BPM STANDARD_DEVIATION 6.1 • n=10 Participants	60.7 BPM STANDARD_DEVIATION 8.2 • n=115 Participants
PR Interval	182.4 ms STANDARD_DEVIATION 23.9 • n=93 Participants	178.4 ms STANDARD_DEVIATION 16.2 • n=4 Participants	162.3 ms STANDARD_DEVIATION 16.5 • n=27 Participants	159.1 ms STANDARD_DEVIATION 15.5 • n=483 Participants	164.4 ms STANDARD_DEVIATION 15.0 • n=36 Participants	171.6 ms STANDARD_DEVIATION 19.4 • n=10 Participants	169.7 ms STANDARD_DEVIATION 19.2 • n=115 Participants
QRS Duration	90.1 ms STANDARD_DEVIATION 7.7 • n=93 Participants	82.9 ms STANDARD_DEVIATION 8.2 • n=4 Participants	87.1 ms STANDARD_DEVIATION 5.8 • n=27 Participants	84.7 ms STANDARD_DEVIATION 6.7 • n=483 Participants	85.4 ms STANDARD_DEVIATION 11.5 • n=36 Participants	87.3 ms STANDARD_DEVIATION 9.4 • n=10 Participants	86.3 ms STANDARD_DEVIATION 8.4 • n=115 Participants
QTc (Fridericia's heart rate corrected QT interval)	386.0 ms STANDARD_DEVIATION 20.2 • n=93 Participants	386.5 ms STANDARD_DEVIATION 17.8 • n=4 Participants	383.9 ms STANDARD_DEVIATION 17.1 • n=27 Participants	393.3 ms STANDARD_DEVIATION 20.0 • n=483 Participants	387.1 ms STANDARD_DEVIATION 13.7 • n=36 Participants	397.1 ms STANDARD_DEVIATION 26.1 • n=10 Participants	389.0 ms STANDARD_DEVIATION 19.2 • n=115 Participants
J-Tpeakc (heart rate corrected J-Tpeak interval)	227.7 ms STANDARD_DEVIATION 22.7 • n=93 Participants	239.4 ms STANDARD_DEVIATION 22.4 • n=4 Participants	231.0 ms STANDARD_DEVIATION 14.5 • n=27 Participants	238.7 ms STANDARD_DEVIATION 20.3 • n=483 Participants	229.5 ms STANDARD_DEVIATION 24.2 • n=36 Participants	239.7 ms STANDARD_DEVIATION 29.4 • n=10 Participants	234.3 ms STANDARD_DEVIATION 22.3 • n=115 Participants
Tpeak-Tend interval	68.7 ms STANDARD_DEVIATION 7.9 • n=93 Participants	65.1 ms STANDARD_DEVIATION 6.6 • n=4 Participants	65.7 ms STANDARD_DEVIATION 7.9 • n=27 Participants	69.7 ms STANDARD_DEVIATION 8.7 • n=483 Participants	72.5 ms STANDARD_DEVIATION 6.4 • n=36 Participants	70.6 ms STANDARD_DEVIATION 14.8 • n=10 Participants	68.7 ms STANDARD_DEVIATION 9.2 • n=115 Participants

PRIMARY outcome

Timeframe: 3 days

Population: Placebo data was used in the statistical analysis to account for placebo effect. Chloroquine, and dofetilide and diltiazem data were collected but not part of the primary J-Tpeakc analysis. The underlying raw data (available at https://doi.org/10.13026/C2967M) were the input in the statistical analysis. Summary included per PRS review team request.

Outcome measures

Outcome measures
Measure	Ranolazine n=10 Participants Ranolazine 1500 mg two times per day for 2.5 days Ranolazine: Ranolazine 1500 mg orally two times per day for 2.5 days	Verapamil n=10 Participants 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 Verapamil: 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 / Ritonavir n=10 Participants Lopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days Lopinavir / Ritonavir: Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days	Chloroquine Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 Chloroquine: Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses)	Placebo n=10 Participants Placebo capsules Placebo: Placebo (administered orally)	Dofetilide and Diltiazem 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. Dofetilide and Diltiazem: 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.	Diltiazem+Dofetilide Data from the diltiazem and dofetilide period of the crossover part: 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.
Change From Baseline J-Tpeakc With "Balanced Ion Channel" Drugs (Ranolazine, Verapamil, Lopinavir / Ritonavir)	-8.3 ms Interval -66.4 to 23.6	-7.8 ms Interval -58.1 to 11.4	-11.5 ms Interval -50.7 to 47.4	—	-10.9 ms Interval -81.2 to 14.7	—	—

PRIMARY outcome

Timeframe: 3 days

Population: Ranolazine, verapamil, lopinavir/ritonavir, and dofetilide and diltiazem data were collected but not part of the primary QTc analysis. The underlying raw data (available at https://doi.org/10.13026/C2967M) were the input in the statistical analysis. Median and range summary included per PRS review team request.

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

Outcome measures

Outcome measures
Measure	Ranolazine Ranolazine 1500 mg two times per day for 2.5 days Ranolazine: Ranolazine 1500 mg orally two times per day for 2.5 days	Verapamil 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 Verapamil: 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 / Ritonavir Lopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days Lopinavir / Ritonavir: Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days	Chloroquine n=10 Participants Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 Chloroquine: Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses)	Placebo n=10 Participants Placebo capsules Placebo: Placebo (administered orally)	Dofetilide and Diltiazem 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. Dofetilide and Diltiazem: 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.	Diltiazem+Dofetilide Data from the diltiazem and dofetilide period of the crossover part: 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.
Change From Baseline QTc With "Predominant hERG" Blocking Drug (Chloroquine)	—	—	—	17.7 ms Interval -24.3 to 71.9	-9.3 ms Interval -48.3 to 27.6	—	—

PRIMARY outcome

Timeframe: 3 days

Population: QTc, J-Tpeakc, and drug concentration data from all subjects in the dofetilide and diltiazem arm. Ranolazine, verapamil, lopinavir/ritonavir, chloroquine, and placebo data were collected but not part of this analysis (see SAP). The underlying raw data were the input in the statistical analysis. Summary included per PRS review team request.

* 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.