A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Dose Escalation Study Evaluating Safety and Pharmacokinetics of VX-983 Followed by an Open-Label, Randomized, Crossover Study to Estimate the Effect of Steady State Administration of VX-983 on the Pharmacokinetics of a Single, Oral Dose of Midazolam in Healthy Adult Subjects

VX-983 is a new investigational compound that may eventually be used for the
treatment of Cystic Fibrosis. Cystic fibrosis is a genetic disorder that cause
the body to produce unusually thick mucus. The thick mucus results in
malfunction of organs like the lungs, pancreas and liver.
VX-983 is not registered as a drug and this is the first time that this
compound is being given to humans.

The study will consist of three parts, part A, B and C. The main purpose of the
study is to investigate to what extent VX-983 is safe and tolerated. In
addition, it will be investigated how quickly and to what extent VX-983 is
absorbed and eliminated from the body (this is called pharmacokinetics). In
part A single ascending doses will be investigated and in part B multiple
ascending doses will be investigated. In part C the effect of VX-983 on the
absorption and elimination of midazolam from the body will be investigated.

Part A:
The study will consist of 1 period during which you will stay in the clinical
research centre in Zuidlaren for 6 days (5 nights).
During the study you will receive VX-983 or inactive formulation (placebo) in
an oral suspension after 8 hours of fasting (no food or drinks) with 240 mL of
tap water. Six participants will receive VX-983 and 2 participants will receive
placebo in each group. Before and after the administration of the study
medication a Listerine strip will be administered. This is a small, paper-thin
strip that dissolves on the tongue and gives a strong mint taste; which will
mask the bitter taste of study medication.
Whether you will receive the active drug or placebo will be determined by
chance.

Part B:
The study will consist of 1 period during which you will stay in the clinical
research centre in Zuidlaren for 15 days (14 nights).
During the study you will receive VX-983 or inactive formulation (placebo) in
an oral suspension after 8 hours of fasting (no food or drinks) with 240 mL of
tap water. Six participants will receive VX-983 and 2 participants will receive
placebo in each group. Before and after the administration of the study
medication a Listerine strip will be administered. This is a small, paper-thin
strip that dissolves on the tongue and gives a strong mint taste; which will
mask the bitter taste of study medication.
Whether you will receive the active drug or placebo will be determined by
chance.

Part C:
The study will consist of 2 periods during which you will stay in the clinical
research centre in Zuidlaren for 5 days (4 nights) and 12 days (11 nights). The
time interval between the different periods (from discharge first period to
admission second period) is 5 days. The time interval between the last dose of
study drug of the first period and the first dose of study drug in period 2
will be a minimum of 7 days.
During the study you will receive VX-983 or midazolam in an oral suspension
after 8 hours of fasting (no food or drinks) with 240 mL of tap water. Before
and after the administration of the study medication a Listerine strip will be
administered. This is a small, paper-thin strip that dissolves on the tongue
and gives a strong mint taste; which will mask the bitter taste of study
medication.

Part A: single dose of VX 983 or placebo after 8 hours fasting period in the
form of an oral suspension.
Part b: multiple doses of VX 983 or placebo after 8 hours fasting period in the
form of an oral suspension.
Part C: treatment A: On Day 1 a single oral dose of 2 mg midazolam will be
administered; treatment B: On Day 1 through 9 an oral dose of VX-983 will be
administered. On Day 10 VX-983 is administered together with a single oral dose
of 2 mg midazolam.

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

As VX-983 will be administered to men for the first time in this study, so to
date adverse effects in men have not been reported. VX-983 has been studied in
animals. It was generally well tolerated by animals (rats and dogs). After
administration of very high doses, beyond what will be administered in this
study, for several weeks the most frequently seen adverse effect was a decrease
in food consumption with weight loss, and less frequently diarrhea, vomiting,
decreased activity and a lack of voluntary coordination of muscle movements
(ataxia).

After the administration of Midazolam® one will probably become very sleepy for
the first few hours. The most frequent adverse effects reported are muscle
weakness, dizziness, memory loss and gastrointestinal complaints.