A multi-center, randomized, double-blind study to compare the efficacy and safety of cadazolid versus vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD).;and substuy protocol:;A multi-center sub-study to validate the CDAD-DaySyms (Clostridium difficile-associated diarrhea - Daily Symptoms) PRO in sub CDAD participating in study AC-061A301 or AC-061A302.

Clostridium difficile-associated diarrhea (CDAD) is an infectious disease of
the gastrointestinal tract. CDAD usually occurs in patients with a history of
antibiotic use that allows C. difficile to grow and elaborate virulent toxins
that can cause intestinal inflammation and diarrhea.
CDAD incidence has been increasing in recent years and disease severity and
mortality has also been increasing.
Several factors, including the 027/BI/NAP1 hypervirulent strain and the
recurrence rate, have contributed to the overall morbidity and mortality of
CDAD and have resulted in the re-emergence of C. difficile as a major global
health problem. New drug therapy that reduces recurrence rates, or improves
outcomes for patients infected with the hypervirulent strain or those with
severe disease, remains a significant unmet medical need.

Primary objective
To determine whether the clinical response after 10-day oral administration of
cadazolid is non-inferior to oral vancomycin in subjects with CDAD.

Secondary objectives
To determine whether oral administration of cadazolid for 10 days is superior
to oral vancomycin in the sustained clinical response of subjects with CDAD.
To determine whether the resolution of diarrhea (ROD) is more rapid with oral
administration of cadazolid compared to vancomycin.
To determine whether CDAD symptoms, as reported by the subject, show larger
improvements from baseline with oral administration of cadazolid compared to
vancomycin.

Meta-analysis objective
To determine whether oral administration of cadazolid for 10 days is superior
to oral vancomycin in the sustained clinical response of subjects with CDAD due
to hypervirulent strains.

Safety objective
To determine safety and tolerability of an oral administration of cadazolid
compared to vancomycin. Exploratory objectives are described in the core
protocol.

This is a prospective, multi-center, double-blind, double-dummy, randomized,
parallel group, group sequential, active controlled, Phase 3 study.

Screening Period starts with the signature of the informed consent form (ICF)
and ends with subject randomization (within 24 hours of the signature of the
ICF).

Treatment Period starts immediately after randomization with the first dose of
study drug and ends on the day of the last dose of study drug (EOT) 10 days
later.
Follow-up Period starts after the last dose of study drug and ends
approximately 30 days after the last dose of study drug (Visit 5).

Re-treatment extension with cadazolid: Subjects who experience a recurrence and
provide consent may enter a re-treatment extension with cadazolid consisting of
a 10-day treatment of cadazolid followed by an approximately 30-day follow-up
period.

Subject participation in the study will be up to 44 days; up to 88 days for
subjects participating in the re-treatment extension with cadazolid.

Investigational drug Cadazolid 250 mg or matching placebo granules for oral
suspension twice daily with or without food.
Comparator Oral vancomycin 125 mg or matching placebo capsules 4 times daily
with or without food.

CORESTUDY [AND RETREATMENT EXTENSION]

The study medication and procedures have risks and discomforts. In any
clinical research study there is the chance of experiencing side effects to the
study medication. Also with any anti-bacterial medication, overgrowth of
bacteria that are not killed could lead to treatment failure. It is possible
that complications and side effects of cadazolid, which are still unknown at
this time, may occur.
The most common side effects reported for adults treated with the same
cadazolid dose, or a higher dose, were: headache, dizziness, confusion, gas,
indigestion, itching.

The following side effects were most frequently reported in adults treated with
vancomycin: nausea, belly or stomach pain, low potassium, diarrhea, vomiting,
gas, fever, headache, swelling of body tissue (usually in the legs), back pain,
tiredness.
Kidney failure, chronic kidney disease and increased levels of creatinine have
been reported with the use of vancomycin, occurring mostly in patients who
receive very high doses of vancomycin given by a needle inserted into a vein
(intravenously), have an underlying kidney disease, or who are on other
medications associated with kidney disease. Blood tests will be done to monitor
the kidney function during the study and after the study treatment is stopped.
The risk of having kidney problems is higher for adults who are more than 65
years old.

More information about risks and discomforts related to the study medication
and procedures.

Cadazolid
Side effects may occur at the dose of cadazolid that is given in this study.
The most common side effects reported for 62 adults with C.diff associated
diarrhea treated with the same cadazolid dose or a higher dose were:
• Headache 8%
• Dizziness 5%
• Confusion 3%
• Gas 3%
• Indigestion 3%
• Itching 3%
In animals treated with cadazolid, slight and reversible increases in liver
function tests were observed at doses higher than the dose that will be given
in this study. In some patients treated with cadazolid, small and reversible
increases in liver function tests have been observed.
In laboratory testing on cells, genotoxic effects (alteration of genetic
information) were observed at doses higher than the dose of cadazolid that will
be given during this study.

Vancomycin
The following side effects were most frequently reported in 260 adults treated
with vancomycin for C.diff associated diarrhea:
• Nausea 17%
• Belly or stomach pain 15%
• Low potassium 13%
Other commonly reported side effects for vancomycin included:
• Diarrhea 9%
• Vomiting 9%
• Gas 8%
• Fever 9%
• Headache 7%
• Swelling of body tissue, usually in the legs 6%
• Back pain 6%
• Tiredness 5%
Kidney failure, chronic kidney disease and increased levels of creatinine have
been reported with the use of vancomycin, occurring mostly in patients who
receive very high doses of vancomycin given by a needle inserted into a vein
(intravenously), have an underlying kidney disease, or who are on other
medications associated with kidney disease. Hearing loss has been reported with
vancomycin, occurring mostly in patients who receive very high doses of
vancomycin given by a needle inserted into a vein (intravenously), have an
underlying hearing loss, or who are on other medications associated with
hearing loss.

Study Procedures
There is a slight risk of pain or bruising and infection when blood is drawn.
Some subjects may experience lightheadedness or fainting during or after having
their blood drawn.
For the electrocardiogram (ECG), electrodes will be placed on the body using a
weak glue or tape and there is a risk of skin irritation when the electrodes
are removed.

Pregnancy
Information about risks, precautions and prevention related to pregnancy
The safety of cadazolid during pregnancy is not known. Research in animals
investigating whether the drug can cause abnormalities of the embryo/foetus is
still ongoing.
Women cannot take part in this study if they are pregnant, or if they are
nursing (breastfeeding). Women who are able to have children, must use a
reliable form of birth control throughout the study and up to 30 days after
stopping taking study medication.
Therefore, they can only participate in this study if they are postmenopausal,
surgically or naturally sterile, or are using one of the following method of
contraception:
• Diaphragm, cap or contraceptive sponge with a spermicide used in combination
with condoms with or without spermicide.
• Intra-uterine devices (IUD)
• Injectable contraceptive agents, levonorgestrel implants, or transdermal
contraceptive hormone patches, provided they have been used for at least one
month prior to the start of study drug.
• Sterilization method such as tubal ligation or partner's vasectomy
Oral contraceptives require additional methods to be used as diarrhea could
affect how well they work. In this case you must also use a diaphragm, cap or
contraceptive sponge with a spermicide in combination with condoms with or
without spermicide.

SUBSTUDY [PRO]

There is no risk of physical harm related to participating in this optional
sub-study; however, you may feel uncomfortable sharing personal information
about your symptoms of C. Diff associated diarrhea.