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A Multinational, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Trial to Investigate Safety and Efficacy of Tibolone (Org OD14) in Women With Climacteric Symptoms and a History of Breast Cancer

Phase 3
75 Years
Not Enrolling
Breast Cancer, Climacteric Symptoms

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Trial Information

A Multinational, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Trial to Investigate Safety and Efficacy of Tibolone (Org OD14) in Women With Climacteric Symptoms and a History of Breast Cancer

A growing proportion of women diagnosed with early stage breast cancer seek help with
vasomotor and sexual complaints. Frequently, these symptoms result from adjuvant cancer
treatment, irrespectively whether this is hormonal (e.g. tamoxifen, aromatase inhibitors),
cytotoxic, or surgical (oophorectomy) in nature. Estrogen-containing hormone therapy is
effective, but considered unsafe. Non-hormonal therapy is less effective. Tibolone, which
does not increase mammographic breast density, has proven to be effective and thus could be
an important treatment option for women persistently seeking help.

The objective of this trial is to demonstrate safety, efficacy and tolerability of oral 2.5
mg tibolone daily in breast cancer patients, who, after surgery, have no evidence of disease
and who suffer from climacteric complaints. Primary study endpoint is breast cancer
recurrence, including primary contralateral breast cancer. Secondary outcome variables
include menopausal symptoms, bone mineral density and health-related quality of life.

Patients were eligible for this study when they had been surgically treated within the
previous 5 years for histologically confirmed T1-3, N0-2, M0 breast cancer and had to have
vasomotor symptoms, with a last menstruation at least 12 months before (or bilateral

The LIBERATE Trial has been designed to show non-inferiority of tibolone compared to
placebo. Adequate sample size was estimated to be at least 1500 subjects in each arm,
assuming a breast cancer recurrence rate of 5% per year in the first 3 years and an dropout
rate of 5% per year.

The LIBERATE Study has successfully included the appropriate number of women with the proper
risk profile so that significant results can be obtained in relation to safety and efficacy
of tibolone in breast cancer patients with menopausal complaints.

Inclusion Criteria:

- Histologically confirmed and surgically treated invasive breast carcinoma (T1/2/3
N0/1/2 M0), irrespective of hormonal (estrogen/progestogen) receptor status.

- Last menstrual bleeding at least 12 months before the start of the study or
ovariectomized or hysterectomized or currently being treated with gonadotropin
releasing hormone analogs.

- Vasomotor symptoms whether related to natural menopause, ovariectomy, or to breast
cancer therapy (chemotherapy, tamoxifen, aromatase inhibitors or other anticancer

- In subjects with an intact uterus, a 'normal' endometrium, defined as:

1. in tamoxifen users: absence of endometrial polyps

2. in non-tamoxifen users: double layer endometrial thickness <=4 mm as assessed by
TVUS or double layer endometrial thickness >4 mm and <=8 mm as assessed by TVUS
plus an endometrial biopsy result of inactive/atrophic.

- Voluntary written informed consent and willing and able to make reasonable efforts to
meet all clinical trial requirements.

Exclusion Criteria:

- Age >75 years at baseline.

- Ductal carcinoma in situ (DCIS) of the breast without the existence of invasive
breast carcinoma.

- Invasive breast carcinoma having a tumor of any size with direct extension to chest
wall or skin (T4) and/or having metastasis to ipsilateral mammary lymph node(s) (N3)
and/or having presence of distant metastasis (M1).

- Surgical treatment of the primary breast cancer >5 years ago.

- History or presence of residual or recurrent breast cancer.

- History or presence of endometrial cancer.

- History or presence of any other malignancy (besides breast cancer and endometrial
cancer) within the past 5 years, except for adequately treated basal cell carcinoma
of the skin.

- Diagnostic findings suspicious for any malignancy.

- Double layer endometrial thickness >8 mm as assessed by TVUS in subjects not being
treated with tamoxifen.

- Final diagnosis of endometrial biopsy different from inactive/atrophic

- Existence of endometrial polyps as demonstrated by TVUS.

- Undiagnosed vaginal bleeding.

- Abnormal cervical smear (corresponding to PAP IIb or higher)

- Any previous or current unopposed estrogen administration in women with an intact
uterus (occasional use of estrogen-containing vaginal cream was allowed after an
appropriate washout period - see below).

- Use of systemic estrogens and/or progestogens (including intra-uterine progestogen
therapy) and/or tibolone and/or phytoestrogens within 8 weeks prior to baseline; use
of transdermal hormone therapy and/or local estrogen applications and/or non-hormonal
medication for vasomotor symptoms within 4 weeks prior to baseline.

- Use of progestogen implants or injections and/or estrogen/progestogen injectable
therapy within the past 6 months.

- Use of estrogen implants or injections within the past 5 years.

- Use of raloxifene hydrochloride and/or any non-registered investigational drug within
the last 8 weeks.

- Active deep vein thrombosis, thromboembolic disorders, or a documented history of
these conditions.

- Severe liver disorders.

- Abnormal laboratory values considered to be clinically relevant by the investigator.

- Any disease or condition that is clinically relevant and which, in the opinion of the
investigator, would jeopardize the subject's well-being during the course of the

- Known hypersensitivity to tibolone or any of its components

- Known or suspected pregnancy

- Age <40 years at baseline and planned breast cancer therapy <2 years after baseline

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Outcome Measure:

To show non-inferiority in breast cancer recurrence of tibolone 2.5 mg versus placebo in women with climacteric symptoms who have been surgically treated for primary breast cancer within the last 5 years

Outcome Time Frame:

At clinical completion

Safety Issue:



Australia: National Health and Medical Research Council

Study ID:




Start Date:

May 2002

Completion Date:

October 2007

Related Keywords:

  • Breast Cancer
  • Climacteric Symptoms
  • Breast cancer
  • Tibolone
  • Climacteric symptoms
  • Breast Neoplasms