A Phase 1, Randomized, Placebo- and Active-Controlled, Double-Blind, Parallel, Electrocardiogram Study to Evaluate the Effect of VX-661 on the QT/QTc Interval in Healthy Subjects

VX 661 is a new investigational compound that may eventually be used for the
treatment of cystic fibrosis (CF). CF is a genetic disorder that causes the
body to produce unusually thick mucus. The thick mucus results in malfunction
of organs like the lungs, pancreas and liver.

In the human body, the cystic fibrosis transmembrane conductance regulator
(CFTR; this is a protein that can be found on the membrane of cells) plays an
important role in the transport of salt and water in and out of cells. In CF,
this protein does not work correctly or it is not produced sufficiently. As a
result, the transport of salt and water in and out of cells is disturbed and
mucus will become unusually thick. VX-661 is thought to improve CFTR
functioning by modifying folding of the protein structure.

The purpose of Part A is to investigate how safe the study compound is and how
well the study compound is tolerated. The study will also investigate how
quickly and to what extent the compound is absorbed into and eliminated from
the body (this is called pharmacokinetics).

The purpose of Part B is to investigate if VX-661 has an effect on the
electrical activity of the heart. In addition, it will be investigate the
safety and tolerability of VX-661. The study will also investigate how quickly
and to what extent VX-661 is absorbed into and eliminated from the body (this
is called pharmacokinetics).

Part A:
The actual study will consist of 1 period during which you will stay in the
clinical research center in Zuidlaren for 12 days (11 nights).
On Days 1 to 7, you will receive VX-661 or inactive formulation (placebo) as
oral tablets with 240 milliliters of tap water. On all dosing days, you are not
allowed to eat from at least 8 hours prior to study compound administration; on
Days 1 and 7, food is also not allowed up to 4 hours after study compound
administration. On all dosing days, water will not be allowed from 2 hours
before to 2 hours after study compound administration (except for the 240
milliliters of tap water taken with the tablets). On Days 2 to 6, you will
receive a breakfast after study compound administration. On all dosing days, at
4 hours after dosing, you will receive a lunch, which you will need to consume
entirely within 30 minutes.

Part B:
The actual study will consist of 1 period during which you will stay in the
clinical research center in Zuidlaren for 18 days (17 nights).
During the study you will receive VX-661, VX-661-matching placebo, moxifloxacin
and/or moxifloxacin matching placebo as oral tablets with 240 milliliters of
tap water. Administration will be done according to the schedule given in
Section *How much of the study compound will I receive?* On all dosing days,
you will have to ingest all tablets within a period of 5 minutes.
On all dosing days, you are not allowed to eat from at least 8 hours prior to
study compound administration. On Days -1, 1, 7, 14 and 15 you are also not
allowed to eat up to 4 hours after study compound administration. On Days 2 to
6 and Days 8 to 13 you will receive a breakfast after study compound
administration. On all dosing days, at 4 hours after dosing, you will receive a
lunch, which you will need to consume entirely within 30 minutes.

Part A:
On Days 1 to 7 you will receive VX-661 or placebo once daily as oral tablets. A
placebo is a tablet without the active ingredient. Whether you will receive
VX-661 or placebo will be determined by chance. In each group, 8 volunteers
will receive VX-661 and 2 volunteers will receive placebo. Neither you nor the
study doctor will know if VX-661 or placebo will be dosed; we call this *the
study is blinded*. However, information on the administration of the study
compound will be present in the clinical research center, in sealed envelopes,
which can be opened in case of emergency.

Group Day Treatment How often
1 1 to 7 VX-661 200 milligrams or placebo (4 tablets)
Once daily
2 1 to 7 VX-661 300 milligrams or placebo (6 tablets)
Once daily
3 (optional) 1 to 7 VX-661 (dose and number of tablets to be determined) or
placebo Once daily


Part B:
In this study, you will receive either VX-661, VX-661-matching placebo,
moxifloxacin and/or moxifloxacin matching placebo; all will be administered as
oral tablets. A placebo is a tablet without the active ingredient.
Treatments are planned as follows:

Day(s) Treatment A
-1 VX-661 or matching placebo (2 tablets)
1 VX-661 100 milligrams (2 tablets) and moxifloxacin or matching placebo (1
tablet)
2 to 7 VX-661 100 milligrams (2 tablets) once daily
8 to 14 VX-661 once daily (dose level and number of tablets to be determined
based upon Part A results; as soon as the dose level is available, all subjects
in Part B will be informed by an amendment to this form)
15 Moxifloxacin or matching placebo (1 tablet)

Day(s) Treatment B
-1 VX-661 or matching placebo (2 tablets)
1 VX-661 or matching placebo (2 tablets) and moxifloxacin 400 milligrams (1
tablet)
2 to 7 VX-661 or matching placebo (2 tablets) once daily
8 to 14 VX-661 or matching placebo once daily (number of tablets same as number
of VX-661 tablets for Treatment A)
15 Moxifloxacin or matching placebo (1 tablet)

Day(s) Treatment C
-1 VX-661 or matching placebo (2 tablets)
1 VX-661 or matching placebo (2 tablets) and moxifloxacin or matching placebo
(1 tablet)
2 to 7 VX-661 or matching placebo (2 tablets) once daily
8 to 14 VX-661 or matching placebo once daily (number of tablets same as number
of VX-661 tablets for Treatment A)
15 Moxifloxacin 400 milligrams (1 tablet)

Procedures: pain, light bleeding, heamatoma, possibly an infection.

Single and multiple doses of VX-661 given alone or in combination with
ivacaftor (an approved drug for the treatment of some patients with CF) have
been studied in 106 healthy volunteers. Safety results from these studies
indicate that VX-661 was generally well tolerated at single doses up to 300
milligrams, at multiple doses up to 200 milligrams once daily for 28 days, and
as a fixed dose combination of 50 milligrams VX-661 with 150 milligrams
ivacaftor. Most adverse effects reported by volunteers in these studies were
mild or moderate in severity. Adverse effects reported included: elevation of
liver enzymes (values had returned to normal within approximately 1 week),
constipation, back pain and pain in extremity, headache, diarrhea and contact
dermatitis.

Moxifloxacin is known to have the following side effects: temporary changes in
the electrical activity of the heart, palpitations, inflammation of the
tendons, fainting spells, dizziness or lightheadedness, allergic reactions and
convulsions.