Biostatistics and Treatment evaluation Unit
Cocculine Synopsis
Study Code: Cocculine
Study ID: ET2005-028
TITLE
Placebo-controlled Evaluation of Homeopathic Remedy
(Cocculine®) Efficacy in the Management of Nausea After Adjuvant
Chemotherapy in Non Metastatic Breast Cancer
PRINCIPAL INVESTIGATOR
TRIAL LOCATION
Isabelle Ray-Coquard, MD, PhD
France
SPONSOR
Centre Léon Bérard
28 Rue Laennec
69008 Lyon, France
DESIGN
Purpose
OBJECTIVES
Randomized, multicentric, placebo-controlled, with 2 parallel arms
Phase III study
Chemotherapy-induced nausea and vomiting (CINV) remains a
major problem that seriously impairs quality of life (QoL) of breast
cancer patients The purpose of the study is to determine whether
a homeopathic remedy (Cocculine®) is effective in the prevention
of chemotherapy-induced nausea in non metastatic breast cancer.
Primary objective
To evaluate against a placebo the efficacy of Cocculine®
administered as an adjunct to conventional treatments
(corticosteroids and 5-HT3 receptor antagonists) for the
management of nausea induced by a 1st course of adjuvant CT
with FAC50, FEC100 or TAC in patients with non-metastatic breast
cancer.
Secondary objectives are to test:
 the persistence of Cocculine® efficacy over the 2nd and 3rd CT
courses
 the contribution of Cocculine® to the global management of
nausea and vomiting during adjuvant CT
 patient compliance with Cocculine® dose.
STUDY POPULATION
Main selection criteria
Inclusion Criteria
 Women with histologically proven non metastatic breast cancer
 No previous chemotherapy
 Treatment planning including 6 adjuvant CT courses with the
first 3 being necessarily of the FAC50, FEC100 or TAC type
 Age>= 18 years
 ECOG performance status (PS) <= 2 (WHO scale)
 Patient able to read and understand French
 Written, voluntary, informed consent
Exclusion Criteria
 Previous treatment with chemotherapy (including neo-adjuvant
chemotherapy for breast cancer)
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Cocculine Synopsis
 Previous malignancies (except basal cell skin cancer or cervical
cancer in situ or any other curatively treated malignancy in
complete remission for more than 5 years)
 Contraindication to corticosteroids or 5-HT3 receptor
antagonists
 Treatment with Cocculine® or any other anti-emetic drug in the
15 days before inclusion
 Pregnant or lactating women
 Follow-up impossible for social, geographical, familial or
psychological reasons
 Patients who cannot be contacted by phone
STUDY TREATMENTS and
ASSESSMENTS
Eligible patients will be randomly allocated before the start of the
chemotherapy (CT) cure to one of the 2 treatments arms:
1. Cocculine® Arm: 12 tablets must be taken in 3 days at
each of the CT courses: 2 on the day before evening of the
CT courses; 2 on the morning, noon and evening of the CT
courses; 2 on morning and noon of the day after the CT
courses.
2. Placebo Arm: 12 tablets must be taken in 3 days at each of
the CT courses: 2 on the day before evening of the CT
courses; 2 on the morning, noon and evening of the CT
courses; 2 on morning and noon of the day after the CT
courses.
The first 3 cycles of chemotherapy are required to be FAC50
(5-Fluoruracil 500 mg/m2 + adriamycin [doxorubicin] 50 mg/m2 +
cyclophosphamide 500 mg/m2), FEC100 (5-Fluoruracil 500 mg/m2
+ epirubicin 100 mg/m2 + cyclophosphamide 500 mg/m2) or TAC
(Taxotere [Docetaxel] 75 mg/m2 + adriamycine 50 mg/m2 +
cyclophosphamide 500 mg/m2).
A standard anti-emetic treatment will be given to all patients:
ondansetron 8 mg (or granisetron 3 mg in case of intolerance to
ondansetron) and methylpredinosolone 80 mg.
To assess efficacy, a self-assessment booklet composed of the FLIE
questionnaire and a specific diary will be given to patients. The
self–administered FLIE questionnaire is composed of two
dimensions (nausea and vomiting) each with 9 items. Each item
consists of a horizontal Visual Analogical Scale (VAS) of 100 mm
graduated from 1 (a lot) to 7 (not at all). No or minimal impact on
daily life is defined as an average FLIE item score > 6. Patients
completed the FLIE questionnaire on Day 6 of the first 3
chemotherapy cycles. Patients will be also provided with a daily
diary to record i) intake of study drug, ii) the occurrence and
intensity of nausea during the first 24 hours and over days 2 to 5
following chemotherapy and the number of vomiting episodes,
and iii) use of any rescue antiemetic medications. All patients will
be contacted by phone on the day-1 (i.e. before the start of
chemotherapy) and if they requested it on day 5 of the first cycle
to ensure that the diary and FLIE questionnaire are completed
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accurately.
In addition, the incidence and severity of AEs (NCI-CTCAE v3.0)
including nausea and vomiting will be recorded by the investigator
at the end of each chemotherapy cycle. Data will be collected until
either the cessation of chemotherapy or the administration of a
maximum of 6 cycles of treatment.
STUDY ENDPOINTS
Primary Outcome Measures
Score of "nausea" calculated using the FLIE questionnaire
(Functional Living index for Emesis with 5-day recall) at the time of
the 1rst adjuvant CT course. The nausea items of FLIE
questionnaire are completed by patients on the 6th day of the 1st
course.
Secondary Outcome Measures
STATISTICAL
CONSIDERATIONS

Score of "vomiting" and global score of "nausea + vomiting"
calculated using the FLIE questionnaire at the time of the 1st,
2nd and 3rd adjuvant CT courses.

Nausea and vomiting items of FLIE questionnaire are
completed by patients on the 6th day of the 1st, 2nd and 3rd
adjuvant CT courses.

Score of "nausea" calculated using the FLIE questionnaire at
the time of the 2nd and 3rd adjuvant CT courses. Nausea items
of FLIE questionnaire are completed by patients on the 6th day
of the 2nd and 3rd adjuvant CT courses.

Patient autoevaluation (D1-D5) of nausea severity using a
visual analogue scale and of the frequency of vomiting during
the 1st, 2nd and 3rd adjuvant CT courses. Visual analogue scales
are completed by patients the 1st five days of the 1st, 2nd and
3rd adjuvant CT courses.

Rate of toxic effects (nausea and vomiting) recorded by
investigators at the end of each of the 6 CT courses. Recorded
by investigators at the end of each of the 6 CT courses

Evaluation of compliance: patient autoevaluation and counting
of remaining tablets. Patients register date and hour of tablets
taking on a diary. Box remaining tablets will be count at the
end of the 6 CT courses.
Sample size determination
The number of patients required to demonstrate a 0.5-point
reduction in nausea on a visual analogue scale, assuming an alpha
risk of 5% in a two-sided test and 85% power, is 396 (198 per arm).
It has been estimated that the enrollment period should be 18
months.
Analysis populations
Analyses will be realized in the intention to treat basis.
General statistical approaches
The primary endpoint is the mean of 9 first FLIE items (at least 5
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Cocculine Synopsis
out of 9 items had to be completed). Scores were compared
between the two arms using the non parametric Mann-Whitney U
test. The number of patients with a mean score > 6 versus the
number of patients with a mean score ≤ 6 will be compared using
Fisher’s exact test.
The emesis score after the 1st, 2nd and 3rd chemotherapy cycles
and the nausea score after the 2nd and 3rd chemotherapy cycles
will be calculated in order to evaluate Cocculine® efficiency over
the first 3 CT cycles.
Vomiting frequency reported on the VAS during the 1st, 2nd and 3rd
CT courses will be compared between the two arms by a Pearson’s
chi-square test (or a Fisher’s exact test, if appropriate).
Compliance will be compared between the 2 arms using the diary
and by counting the amount of drug that remained in its
packaging. AEs will be compared between the two arms over the
6-cycle period with particular attention to nausea or vomiting.
All analyses will be performed using the SAS software, version 9.1
(SAS Institute, Cary, NC).
Study Calendar
Study start: September 2005
Inclusion Period: 18 months
Follow-up duration: a maximum of 18 weeks (i.e. 6 cycles of CT)
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