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BMJ. 2008 January 5; 336(7634): 7–8.
PMCID: PMC2174754
Tibolone

Still waiting and searching for answers

Emilio Maestri, endocrinologist,1 Susanna Maltoni, pharmacist,1 Vittorio Basevi, gynaecologist,1 Annamaria Marata, clinical pharmacologist,1 and Nicola Magrini, head1

Clinicians working in the subject area of menopausal problems are still waiting for answers from trials designed to give results on relevant topics in the treatment of climacteric complaints.

Two important trials were planned (and registered) to define the efficacy and safety of tibolone versus placebo in preventing osteoporotic fractures (LIFT)1 and managing menopausal symptoms in women after treatment for breast malignancy (LIBERATE).2 The start of the two studies received great attention from the media; repeated attention was sparked by every favourable report of the study data and safety monitoring boards (DSMB).

Unfortunately, the facts didn’t match clinicians’ and patients’ expectations. In October 2005 a letter published in the BMJ reported the first unfavourable result for LIFT.3 Women treated with tibolone 1.25 mg showed an increased risk of stroke compared with women treated with placebo.3 (4.26 cases/1000 woman years versus 1.64 cases/1000 woman years, respectively; relative risk 2.59, P=0.01). In March 2006, this increased risk was confirmed (hazard ratio 2.3, P=0.02); a second letter in the BMJ announced that the DSMB decided to stop the trial.4 The letter ended with the declared purpose “to publish a more detailed report,” but no further publication has become available since.

What about LIBERATE? We found some minimal communications on the premature stop of the trial by searching Google (no trace on this trial was found on PubMed). The news appeared on May 2007 on Drug Information Online (drugs.com) and on the Organon website. But after similarly sparse communications about the early halt of the study (because of an excess rate of recurrent breast cancer in patients taking tibolone compared with placebo), no more detailed publication has followed.

The official clinical trial registers do not contain any more information either. According to the WHO and US NIH websites the LIBERATE trial is ongoing (search performed on 28 November 2007).

We need to know the complete data on the safety profile of tibolone as found in the LIFT and LIBERATE trials. Many years after tibolone marketing, data from long term clinical trials on the incidence of relevant outcomes—such as deep venous thrombosis, myocardial infarction, or the risk of breast cancer—are still lacking. The only results from a randomised controlled trial come from the THEBES study,5 in which the incidence of adverse events after two years was strikingly lower than that observed after the two years in other randomised controlled trials on hormone replacement therapy.

We need prompter, fully transparent access to potentially relevant information about drugs’ unfavourable results. Maybe less emphasis should be placed on ongoing studies, interpreted under the optimism bias, which transforms uncertainty into expectations or even positive results, far before the studies’ completion.

Notes

Competing interests: None declared.

References

1. Trial to evaluate tibolone in the treatment of osteoporosis (LIFT). http://clinicaltrials.gov/ct2/show/NCT00519857
2. Livial intervention following breast cancer; efficacy, recurrence and tolerability endpoints (LIBERATE). http://clinicaltrials.gov/ct2/show/NCT00408863
3. Grobbee DE, LIFT Steering Committee. LIFT study to continue as planned. BMJ 2005;331:843-a
4. Cummings SR, for LIFT Steering Committee. LIFT study is discontinued. BMJ 2006;332:667 doi:10.1136/bmj.332.7542.667
5. Archer DF, Hendrix S, Gallagher JC, Rymer J, Skouby S, Ferenczy A, et al. Endometrial effects of tibolone. J Clin Endocrinol Metab 2007;92:911-8. [PubMed]

Articles from BMJ : British Medical Journal are provided here courtesy of BMJ Group