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Trial to Compare the Effects of Tibolone (Livial®) and Continuous Combined Low-Dose Estradiol/Noresterone (Activelle®) (TOTAL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00431093
Recruitment Status : Completed
First Posted : February 5, 2007
Last Update Posted : June 4, 2015
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
The present trial is undertaken to compare the effects of Tibolone with a low-dose HRT regimen.

Condition or disease Intervention/treatment Phase
Menopause Drug: tibolone Drug: low-dose estradiol/noresterone Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 570 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-Blind, Double Dummy, Group-Comparative Trial to Compare the Effects of Livial® and Activelle ® on the Vaginal Bleeding Pattern, Vasomotor Complaints, Vaginal Atrophy, QoL and Sexual Function
Study Start Date : November 2002
Actual Primary Completion Date : March 2005
Actual Study Completion Date : March 2005

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: 1
Drug: low-dose estradiol/noresterone

Activelleâ, estradiol (E2) 1 mg and norethisterone acetate (NETA) 0.5 mg per tablet, was supplied as uncoded tablets.

Subjects were to take 1 Activelleâ tablet and 1 Livialâ-matched placebo tablet, orally, once a day (preferably at the same time).

Other Name: Activelle®

Active Comparator: 2
low-dose estradiol/noresterone
Drug: tibolone
uncoded tablets, at a dose of 2.5 mg per tablet; Subjects were to take 1 Livialâ tablet and 1 -matched Activelleâ placebo tablet, orally, once a day (preferably at the same time).
Other Name: Livial

Primary Outcome Measures :
  1. For the bleeding evaluation, subject will be given a diary card to record the days on which no bleeding, vaginal spotting or bleeding occurs [ Time Frame: starting from baseline and during the whole trial period. ]

Secondary Outcome Measures :
  1. Hot flushes recorded on a daily diary card during the whole trial period. [ Time Frame: Entire trial ]
  2. A mammography to assess breast density and blood samples to determine the changes in endocrine parameters. [ Time Frame: screening and week 48 ]
  3. A vaginal smear to assess the Vaginal Maturation Index and the Karyopycnotic Index results [ Time Frame: Baseline and week 48 ]
  4. Urogenital complaints assessed with the Local Urogenital Complaints Rating Scale. [ Time Frame: At baseline, week 12, week 24 and week 48 ]
  5. Health-related quality of life measured with the Women's Health Questionnaire 36-items (WHQ-36) the McCoy Female Sexuality Questionnaire-Short Form 9-items (MFSQ-SF) collecting prospectively medical resources utilization items [ Time Frame: At baseline and week 48 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years to 64 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Subjects must be healthy and postmenopausal women, >= 45 and < 65 years of age, with an intact uterus.
  • Subjects must have been postmenopausal for less than 15 years.
  • Body Mass Index >18 and =< 32 kg/m2.
  • Voluntary written informed consent is required.

Exclusion Criteria:

  • Any unexplained abnormal uterine bleeding after the menopause.
  • Double layer endometrial thickness = 6 mm as assessed by transvaginal ultrasonography.
  • Treatment with oral estrogen and/or progestogen therapy within 4 weeks prior to screening, or treatment with transdermal therapy and local estrogen applications within 4 weeks prior to screening.
  • Any previous or current unopposed estrogen administration, prior use of estrogen pellets or tamoxifen citrate (occasional use of estrogen-containing vaginal cream is allowed after the appropriate wash-out period is completed). Estrogen combined with sequential administration of progestogen should have been at least 10 days per 28 day cycle.
  • The following wash-out periods apply:

    • 4 weeks for transdermal hormonal treatment, local estrogen applications or other non-hormonal medication known to act on the relief of vasomotor symptoms (e.g. clonidine)
    • 4 weeks for phytoestrogens, tibolone, intra-uterine or oral progestogen and oral estrogen/progestogen therapy
    • 6 months for progestogen implants or injections and estrogen/progestogen injectable therapy.
  • Any subjects who are either using phytoestrogens, tibolone, intra-uterine or oral progestogen, progestogen implants or injections, estrogen/progestogen combination therapy or any other non-hormonal medication known to act on the relief of vasomotor symptoms and who have not observed the appropriate wash-out periods (see previous exclusion criteria).
  • Any serious disease or disorder; or any endocrine disorder; (controlled hypo/hyperthyroidism and diabetes mellitus Type II is allowed).
  • Diseases for which exogenous hormonal steroids are contraindicated.
  • History or presence of any malignancy, except successfully treated nonmelanoma skin cancers.
  • History or presence of cardiovascular or cerebrovascular conditions:

    • thrombophlebitis, thrombosis or thromboembolic disorders.
  • History or presence of liver, gallbladder (subjects who have had a cholecystectomy will not be excluded) or renal disease, epilepsy or classical migraine headaches.
  • History or presence of clinically significant depression or other psychiatric disorders which, in the investigator's judgment, might compromise or confound the subject's participation in the trial.
  • Uncontrolled high blood pressure: systolic pressure > 170 mmHg and/or diastolic pressure > 105 mmHg, measured after 5 minutes in a sitting position.
  • Abnormal cervical Pap smear (corresponding to PAP = III, or LSIL, HSIL, ASCUS, AGCUS in the Bethesda classification)
  • Abnormal, clinically significant results of the mammography.
  • Presence of fibrocystic disease of the breast.
  • Presence of otosclerosis.
  • Known hypersensitivity to any of the ingredients of the trial medication.
  • Any subjects using either steroids, drugs known to affect sexual functioning and mood (antidepressants, psychoactive drugs, sedatives, neuroleptics, narcotics, benzodiazepines), drugs know to interfere with the pharmacokinetics of the steroids (hydantoins, primidone, rifampicin, barbiturates, carbamazepine, griseofulvin, warfarin, ketoconazole, or products containing St. John's wort), or raloxifene hydrochloride. A wash-out period of 4 weeks will apply to subjects using these drugs. Sporadical use of benzodiazepines (twice or less a week) is allowed
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Merck Sharp & Dohme Corp. Identifier: NCT00431093    
Other Study ID Numbers: P06673
C-1755 ( Other Identifier: Schering-Plough )
First Posted: February 5, 2007    Key Record Dates
Last Update Posted: June 4, 2015
Last Verified: June 2015
Additional relevant MeSH terms:
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Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Androgen Antagonists
Hormone Antagonists
Antihypertensive Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Modulators
Anabolic Agents