Clinical Trial Results:
A Phase 1, Open-label, Randomized, Crossover Study to Evaluate the Relative Bioavailability of a Granule Formulation of Tezacaftor and Ivacaftor Compared to a Fixed-dose Combination Tablet in Healthy Adult Subjects
Summary
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EudraCT number |
2020-000689-40 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
08 Nov 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Nov 2021
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First version publication date |
19 Nov 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
VX19-661-012
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Vertex Pharmaceuticals Incorporated
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Sponsor organisation address |
50 Northern Avenue, Boston, Massachusetts, United States,
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Public contact |
Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
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Scientific contact |
Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001640-PIP01-14 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
07 Dec 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 Nov 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Nov 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the relative bioavailability (BA) of a granule formulation of tezacaftor (TEZ)/ivacaftor (IVA) compared to a reference fixed-dose combination (FDC) tablet of TEZ/IVA.
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Protection of trial subjects |
The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Oct 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 16
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Worldwide total number of subjects |
16
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
16
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||
Pre-assignment
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Screening details |
This study was conducted in healthy subjects 19 to 55 years of age. | |||||||||
Period 1
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Period 1 title |
Overall Period
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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TEZ/IVA Sequence 1: First Granules Then Tablet | |||||||||
Arm description |
Subjects received TEZ 50 milligrams (mg)/IVA 75 mg granules on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg fixed-dose combination (FDC) tablet on Day 15 in dosing period 2. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
TEZ/IVA
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Investigational medicinal product code |
VX-661/VX-770
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Other name |
Tezacaftor/Ivacaftor
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Pharmaceutical forms |
Granules, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of TEZ/IVA granule and tablet formulation in the fed state in dosing period 1 and 2 as per the sequence.
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Arm title
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TEZ/IVA Sequence 2: First Tablet Then Granules | |||||||||
Arm description |
Subjects received TEZ 50 mg/IVA 75 mg FDC tablet on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg granules on Day 15 in dosing period 2. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
TEZ/IVA
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Investigational medicinal product code |
VX-661/VX-770
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Other name |
Tezacaftor/Ivacaftor
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Pharmaceutical forms |
Tablet, Granules
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of TEZ/IVA granule and tablet formulation in the fed state in dosing period 1 and 2 as per the sequence.
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Baseline characteristics reporting groups
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Reporting group title |
TEZ/IVA Sequence 1: First Granules Then Tablet
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Reporting group description |
Subjects received TEZ 50 milligrams (mg)/IVA 75 mg granules on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg fixed-dose combination (FDC) tablet on Day 15 in dosing period 2. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEZ/IVA Sequence 2: First Tablet Then Granules
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Reporting group description |
Subjects received TEZ 50 mg/IVA 75 mg FDC tablet on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg granules on Day 15 in dosing period 2. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
TEZ/IVA Sequence 1: First Granules Then Tablet
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Reporting group description |
Subjects received TEZ 50 milligrams (mg)/IVA 75 mg granules on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg fixed-dose combination (FDC) tablet on Day 15 in dosing period 2. | ||
Reporting group title |
TEZ/IVA Sequence 2: First Tablet Then Granules
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Reporting group description |
Subjects received TEZ 50 mg/IVA 75 mg FDC tablet on Day 1 in dosing period 1 followed by TEZ 50 mg/IVA 75 mg granules on Day 15 in dosing period 2. | ||
Subject analysis set title |
TEZ/IVA Granules
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who received TEZ 50 mg/IVA 75 mg granules formulation in sequence 1 or 2.
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Subject analysis set title |
TEZ/IVA FDC Tablet
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who received TEZ 50 mg/IVA 75 mg tablet formulation in sequence 1 or 2.
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End point title |
Maximum Observed Plasma Concentration (Cmax) of TEZ and IVA | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1 up to 144 hours post-dose
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Statistical analysis title |
TEZ: Granules vs TEZ: Tablet | ||||||||||||||||||
Statistical analysis description |
As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
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Comparison groups |
TEZ/IVA Granules v TEZ/IVA FDC Tablet
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||
Method |
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Parameter type |
Geometric Least Squares Mean Ratio | ||||||||||||||||||
Point estimate |
81.5
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
71.4 | ||||||||||||||||||
upper limit |
93.1 | ||||||||||||||||||
Statistical analysis title |
IVA: Granules vs IVA: Tablet | ||||||||||||||||||
Statistical analysis description |
As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
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Comparison groups |
TEZ/IVA FDC Tablet v TEZ/IVA Granules
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||
Method |
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Parameter type |
Geometric Least Squares Mean Ratio | ||||||||||||||||||
Point estimate |
98.2
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
85.5 | ||||||||||||||||||
upper limit |
113 |
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End point title |
Area Under the Concentration Versus Time Curve From the Time of Dosing Extrapolated to Infinity [AUC(0 - inf)] of TEZ and IVA | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1 up to 144 hours post-dose
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Statistical analysis title |
TEZ: Granules vs TEZ: Tablet | ||||||||||||||||||
Statistical analysis description |
As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
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Comparison groups |
TEZ/IVA Granules v TEZ/IVA FDC Tablet
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||
Method |
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Parameter type |
Geometric Least Squares Mean Ratio | ||||||||||||||||||
Point estimate |
93.4
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
88.4 | ||||||||||||||||||
upper limit |
98.7 | ||||||||||||||||||
Statistical analysis title |
IVA: Granules vs IVA: Tablet | ||||||||||||||||||
Statistical analysis description |
As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
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Comparison groups |
TEZ/IVA Granules v TEZ/IVA FDC Tablet
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||
Method |
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Parameter type |
Geometric Least Squares Mean Ratio | ||||||||||||||||||
Point estimate |
105
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
90.7 | ||||||||||||||||||
upper limit |
122 |
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End point title |
Area Under the Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration [AUC(0-tlast)] of TEZ and IVA | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 1 up to 144 hours post-dose
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Statistical analysis title |
TEZ: Granules vs TEZ: Tablet | ||||||||||||||||||
Statistical analysis description |
As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
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Comparison groups |
TEZ/IVA Granules v TEZ/IVA FDC Tablet
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||
Method |
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Parameter type |
Geometric Least Squares Mean Ratio | ||||||||||||||||||
Point estimate |
93.9
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
88.6 | ||||||||||||||||||
upper limit |
99.5 | ||||||||||||||||||
Statistical analysis title |
IVA: Granules vs IVA: Tablet | ||||||||||||||||||
Statistical analysis description |
As this is a cross-over study, actual number of subjects analysed for the statistical comparison was “16” for TEZ/IVA Granules arm and TEZ/IVA FDC Tablet arm. “Number of subjects included in analysis = 32” is reflected due to EudraCT database limitation of summing up the comparison arm numbers.
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Comparison groups |
TEZ/IVA Granules v TEZ/IVA FDC Tablet
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||
Method |
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Parameter type |
Geometric Least Squares Mean Ratio | ||||||||||||||||||
Point estimate |
105
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
90.6 | ||||||||||||||||||
upper limit |
123 |
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 up to Day 21
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
TEZ/IVA Granules
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Reporting group description |
All subjects who received TEZ 50 mg/IVA 75 mg granules formulation in sequence 1 or 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEZ/IVA FDC Tablet
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Reporting group description |
All subjects who received TEZ 50 mg/IVA 75 mg tablet formulation in sequence 1 or 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |