Trial Information

PHASE III, Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Efficacy and Safety of Pregabalin in Prevention and Reduction of Oxaliplatin-induced Painful Neuropathy

1. OBJECTIVES

1.1. Primary Objectives

The primary objective of this study is to evaluate the efficacy of co-administration of
Pregabalin during oxaliplatin infusion in reducing the appearance of both acute and late
onset oxaliplatin-induced painful neuropathy in patients with colorectal cancer.

1.2. Secondary Objectives

The secondary objectives of this study are as follows:

- To compare the pain intensity and interference between the two treatment arms

- To compare the safety profile between the two treatment arms

- To compare quality of life between the two treatment arms

- To compare the percentage of patients with neuropathy between the two treatment groups

- To compare the intensity of neuropathy related to oxaliplatin between the two arms

- To compare the small fiber function and positive sensory signs before and after
treatment with Pregabalin

- To compare mood (depression and anxiety) before and after treatment with Pregabalin in
each treatment arm

- To assess the association between cumulative oxaliplatin dose and time for painful
neuropathy and peripheral sensory neuropathy diagnosis, pain intensity, pain
interference and small fiber function.

TREATMENT PLAN

2.1 Pregabalin Administration

Treatment will be administered on an outpatient basis. Reported adverse events and
potential risks are described in Section 7. Appropriate dose modifications for Pregabalin
are described in Section 6. No investigational or commercial agents or therapies other than
those described below may be administered with the intent to treat the patient's
oxaliplatin-induced painful neuropathy.

Patients will receive either Pregabalin or placebo three days before and three days
following the OX infusion (week 1, 3, and 5 from each of the three cycles, in a total of
nine sessions).

The total daily dose of Pregabalin will be flexible in the first dose, and then, a fixed
dose will be set for each individual. Before the first Ox dose, patients will start on 75mg
bid and will be followed by telephone contact by a research nurse who will instruct them to
optimize the dose of Pregabalin every two days according to the magnitude and profile of
side effects.

The minimum daily dose to allow for entry in the study is 150mg/day upon the first Ox
infusion. Such a "guided" dose escalation will only be performed before the first Ox
infusion and will last for four days. Thereafter, the maximum tolerated dose used before the
first Ox infusion will be used during the three following days and during the rest of the
study. The same protocol will be performed in the placebo group.

After signing the informed consent and agreeing to participate in the protocol, patients
will undergo the "guided" Pregabalin dose escalation for four days. Then, they will receive
Pregabalin for the three days following the first Ox infusion. Thereafter, they will receive
this same Pregabalin dosage for six days during the eight next Ox infusions sessions ie.,
starting three days before and ending on the third day after each Ox infusion session (from
D-3 to D+3)

2.2 Duration of Therapy

In the absence of treatment delays due to adverse event(s), treatment may continue for 3
cycles of FLOX (totalizing nine oxaliplatin infusions) or until one of the following
criteria applies:

Intercurrent illness that prevents further administration of treatment,

Unacceptable adverse event(s),

Patient decides to withdraw from the study, or

General or specific changes in the patient's condition render the patient unacceptable for
further treatment in the judgment of the investigator.

2.3 FLOX administration

Treatment with fluorouracil plus leucovorin and oxaliplatin (FLOX) 28, 29 will be
administered on an outpatient basis.

Patients will receive intravenous (IV) treatment weekly for 6 weeks of each 8-week cycle for
three cycles. Chemotherapy with FLOX is to be given for 3 cycles in both treatment arms.

FLOX regimen includes:

- Oxaliplatin will be administered at a dose of 85mg/m2 IV on weeks 1, 3, and 5 of each
8-week cycle for three cycles.

- 5-Fluorouracil (5-FU) will be administered at a dose of 500mg/m2 IV bolus weekly for 6
weeks (on weeks 1, 2, 3, 4, 5, and 6).

- Leucovorin 20 mg/m2 IV will be administered on weeks 1, 2, 3, 4, 5, and 6.

Drugs to be administered before chemotherapy:

Dexamethasone 20 mg IV and Ondansetron 8mg IV will be administered before chemotherapy
administration. Dexamethasone will be administered on weeks 1, 3, and 5. Ondansetron will be
administered on weeks 1, 2, 3, 4, 5, and 6.

Drugs to be administered after chemotherapy:

Patients will also receive dexamethasone 4 mg P.O. BID for three days and ondansetron 8 mg
P.O. each 8 hours (if necessary) after each dose of the Oxaliplatin (on weeks 1, 3, and 5).

2.4 Duration of Follow-up

Patients will be followed for 6 months after removal from study or until death, whichever
occurs first. Patients removed from study for unacceptable adverse events will be followed
until resolution or stabilization of the adverse event.

2.5 Criteria for study withdraw

After fulfilling all the inclusion criteria and not presenting any exclusion criteria, and
having started on the protocol, patients will be removed from it if at least one of the
conditions bellow is met:

1. Voluntary consent withdraw by the patients, due to any reason;

2. The patient is considered non compliant to the protocol (ie. more than three absences
in regular protocol visits or failure to take Pregabalin for two treatment session with
oxaliplatin.

In all cases of removal, the patient data and reason for removal will be recorded.