- Email: [email protected]
Dose–response analysis of effects of tibolone on climacteric symptoms
BJOG: an International Journal of Obstetrics and Gynaecology October 2002, Vol. 109, pp. 1109 –1114
Dose–response analysis of effects of tibolone on climacteric symptoms M.B. Landgrena, H.J.T. Coelingh Benninkb, F.A. Helmondc,*, S. Engelend Objective To assess the clinically optimal tibolone dose for the relief of climacteric complaints. Design A randomised, double blind, placebo-controlled trial. Setting Twenty-eight centres in Norway, The Netherlands, Sweden and Finland. Population Seven hundred and seventy-five healthy postmenopausal women were randomised to tibolone in a daily dose of 0.625, 1.25, 2.5 or 5.0 mg or placebo for 12 weeks. Methods At baseline, and after 4, 8 and 12 weeks, hot flushes, sweating, vaginal bleeding and adverse experiences were recorded. Main outcome measures Change in frequency and intensity of hot flushes and sweating over 12 weeks. Results From week four onwards, 2.5 and 5.0 mg tibolone were significantly more effective than placebo, regarding the frequency of hot flushes and sweating ( P < 0.001), whereas the 0.625 mg dose was not significantly different from placebo during the study. The frequency of hot flushes with the 1.25 mg dose was statistically significantly different from placebo, only from week eight onwards. The incidence of dropouts due to insufficient therapeutic effect was much higher in the tibolone 1.25 mg group (9.5%) than in the 2.5 (1.9%) and 5.0 mg (1.3%) groups. A dose-related increase in incidence of vaginal bleeding or spotting was observed ( P < 0.0001). Bleeding incidence in the 5.0 mg dose group was about twice as high as in the 2.5 mg dose group. There was no difference in incidence of adverse experiences between the 2.5- and the 1.25 mg dose group. Conclusion A daily dose of 2.5 mg tibolone is the clinically optimal dose for the treatment of climacteric complaints in postmenopausal women. INTRODUCTION Oestrogen replacement therapy has been shown to be effective in alleviating the often distressing features of the menopause, such as hot flushes and sweating. To prevent endometrium stimulation, oestrogen therapy has been combined with progestogens, which may introduce progestogen-related adverse experiences. An attractive approach to hormone replacement therapy (HRT) is offered by tibolone, a compound with tissue-specific effects1, mediated via steroid receptors and enzymatic pathways resulting in positive clinical effects on hot flushes and sweating, bone, vagina, and avoids stimulation of the endometrium.
Several placebo- and active-controlled studies have shown that tibolone in a daily dose of 2.5 mg (Livial) alleviates climacteric complaints such as hot flushes and sweating episodes2, its activity being comparable to that of 0.625 mg conjugated oestrogens3,4 or 2 mg oestradiol5,6. Thus far, only limited published data on the efficacy of other doses of tibolone are available. It has been suggested that doses of tibolone lower than the current marketed formulation might be beneficial for the prevention of bone loss7 – 9. The aim of the present study was to assess the clinically optimal dose of tibolone for HRT in postmenopausal women.
METHODS a
Karolinska Hospital, Stockholm, Sweden b Program Management Section, NV Organon, Oss, The Netherlands c Clinical Development Department, NV Organon, Oss, The Netherlands d Clinical Trials Operations Biometrics, NV Organon, Oss, The Netherlands * Correspondence: Dr F. A. Helmond, International Marketing, KA 4016, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands. D RCOG 2002 BJOG: an International Journal of Obstetrics and Gynaecology PII: S 1 4 7 0 - 0 3 2 8 ( 0 2 ) 0 2 9 2 0 - 8
The study was designed as a multicentre, randomised, double blind, placebo-controlled, dose –response study in postmenopausal women who experience hot flushes and sweating episodes. The study was conducted in 28 centres, located in Sweden (n ¼ 9), the Netherlands (n ¼ 8), Finland (n ¼ 7) and Norway (n ¼ 4). The study was performed between March 1994 and July 1995 and was in full compliance with the Declaration of Helsinki, plus revisions. The study protocol was approved by the ethics committee for each centre, and all subjects had www.bjog-elsevier.com
1110
M.B. LANDGREN ET AL.
given written informed consent before participation in the study. Subjects were selected according to a number of criteria. Included were non-hysterectomised women between 40 and 60 years, with absence of spontaneous vaginal bleeding for at least 10 months and presence of climacteric symptoms (at least one moderate to severe hot flush per day). Body weight had to be between 80% and 130% of the ideal body weight (Metropolitan Life Insurance Company Tables for Women). Women with the following conditions were excluded: history or presence of any malignant disorder, cardiovascular or cerebrovascular disease, thromboembolism/thrombosis, hepatic or renal disease, epilepsy or classical migraine, vaginal bleeding of unknown aetiology, hypertension (systolic BP > 170 mmHg and/or diastolic BP > 105 mmHg), rheumatoid arthritis, diabetes mellitus, hyperlipidaemia (fasting cholesterol > 8.5 mmol/L and/or fasting triglycerides > 2.5 mmol/L), any serious disease or psychiatric disorder, hypersensitivity to oestrogen and/or progestogen, disease for which exogenous hormonal steroids are contraindicated. The use of sex steroids within six weeks, or ethinyloestradiol within the last six months, or hormone implants at any time previously, one or more of the following drugs during the last two months: hydantoins, barbiturates, primidone, carbamazepine, rifampicine, griseofulvin, drugs for the treatment of climacteric symptoms (excluding homeopathic drugs); alcohol abuse and/or drug abuse within the last 12 months and smoking more than 10 cigarettes per day was also a reason for exclusion. After written informed consent was obtained, subjects underwent a general and a gynaecologic examination. Concomitant cholesterol lowering treatment and starting homeopathic drugs during the treatment were not allowed. Study medication was tibolone (oral tablets; NV Organon, Oss, the Netherlands) in a daily dose of 0.625, 1.25, 2.5 (Livial) or 5 mg, or placebo (oral tablets that were identical in appearance). Eligible subjects were numbered consecutively per centre, and received the corresponding treatment number from the randomisation list. Tablet intake and occurrence of vaginal bleeding were recorded in a diary booklet. At baseline, after 4, 8, and 12 weeks, climacteric symptoms were recorded. Frequency of climacteric symptoms was expressed as an average number per 24-hour period in the last week before each assessment. Intensity of climacteric symptoms was scored by the subjects on a five-step self-rating scale adapted from the climacteric symptoms rating scale developed by Collins and Landgren (Karolinska Hospital, Stockholm, Sweden). A combined measure of frequency and intensity of the symptoms was obtained by defining a ‘complete responder’ as a subject having no or at most one mild hot flush or sweating episode per day. In addition, after 12 weeks, a general and gynaecologic examination was performed. The vaginal bleeding pattern (spotting and/or bleeding) and number and nature of adverse experiences were recorded throughout the study period.
The clinically optimal dose was determined by weighing efficacy against side effects. The primary objective was to assess the reduction in the frequency and intensity of hot flushes and sweating episodes achieved by four different doses of tibolone compared with placebo. The secondary objective was to obtain dose – response related data on vaginal bleeding. A sample size of 5 80 evaluable subjects was planned in order to be able to detect a difference of 25% in response rates between placebo and a dose group, with a power of 80% at a significance level of 1.25% (m2 test, with Bonferoni correction for multiple comparisons). A total of 775 (5 155) subjects were recruited to compensate for expected dropouts and non-evaluable subjects. The number of hot flushes and sweating episodes was analysed by non-parametric Cochran – Mantel – Haenszel (CMH) tests, adjusted for centre, for overall and pairwise group differences (dose group versus placebo), using modified ridit scores. The Bonferoni correction for multiple testing was applied to the four pairwise comparisons (i.e. a significance level of 0.0125 was used for each of the four pairwise comparisons). In addition, analysis of covariance, with baseline as covariable, and adjustment of extreme outliers was performed in order to give estimates of treatment differences. Linear trend tests for the doserelated trend were performed using the Mantel – Haenszel m2 test with 1 df based on the equally spaced treatment groups (scores 0, 1, 2, 3, 4 for the respective dose groups). Proportional odds regression analysis was applied to the intensity of hot flushes and sweating episodes. CMH tests were also applied to response rates and occurrence of vaginal bleeding. Comparison between a dose group and placebo with respect to cumulative dropout rates was performed by log-rank tests using Kaplan – Meier estimates. Explorative analyses were performed on response rates using stepwise linear logistic regression to investigate the effects of potential prognostic factors such as age, time since menopause and previous use of HRT.
RESULTS A total of 775 subjects were randomised across the five treatment groups. Five subjects did not start treatment, so the All-Subjects-Treated group consisted of 770 subjects. In total, 740 subjects were evaluable for the All-SubjectsEvaluable group (all treated subjects with at least one postbaseline assessment). Demographic data for this group are presented in Table 1. No differences between the five treatment groups were observed. Of the All-Subjects-Treated group, 99 subjects (12.9%) discontinued. An overview of the number of dropouts per treatment group and reason for discontinuation is given in Table 2. The most frequently reported reasons were insufficient therapeutic effect (55 subjects) and adverse experience-related reasons (36 subjects). Pairwise comparison of D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
DOSE – RESPONSE STUDY WITH TIBOLONE
1111
Table 1. Demographic data and climacteric symptoms at baseline [mean (SD)] for the All-Subjects-Evaluable group. Placebo (n ¼ 143)
Tibolone 0.625 mg (n ¼ 149)
Age (years) [range] 52.9 (3.5) [43 – 60] 52.2 (3.5) Height (cm) 164.2 (6.4) 165.7 Body weight (kg) 67.5 (8.4) 67.2 25.0 (2.6) 24.5 Body mass index (kg/m2) Time since menopause (months) [range] 37.3 (19.9) [0 – 116] 34.1 (18.9) Number of hot flushesa Intensity of hot flushesb None Mild Moderate Severe Very severe Number of sweating episodesa Intensity of sweating episodesb None Mild Moderate Severe Very severe a b
8.1 (4.8)
Tibolone 1.25 mg (n ¼ 143)
2.7 4.7 42.3 37.6 12.8
7.5 (4.9)
9.2 (5.7)
8.2 (5.6)
1.4 3.5 40.6 45.5 9.1
9.9 (17.0)
3.5 9.8 33.6 41.3 11.9
Tibolone 5.0 mg (n ¼ 151)
[40 – 60] 51.6 (3.5) [42 – 58] 51.8 (3.4) [42 – 59] 52.5 (3.2) [43 – 60] (5.9) 164.5 (5.3) 164.8 (5.7) 164.9 (5.9) (8.5) 67.3 (8.9) 67.7 (9.3) 67.7 (9.3) (2.7) 24.8 (2.9) 24.9 (3.0) 24.9 (3.1) [12 – 130] 33.3 (21.4) [6 – 200] 34.0 (21.5) [2 – 214] 35.1 (19.6) [1 – 116]
9.8 (6.6)
1.4 4.2 43.4 40.6 10.5
Tibolone 2.5 mg (n ¼ 154)
4.7 9.4 35.6 38.9 11.4
0.6 6.5 38.3 43.5 11.0
8.1 (5.7)
7.5 (6.2)
4.9 7.0 36.4 41.3 10.5
4.5 10.4 35.7 42.2 7.1
8.2 (5.3)
0 4.0 33.8 47.0 15.2 7.0 (5.2)
4.6 7.3 32.5 41.1 14.6
Defined as total number per 24-hour period; mean (SD). Expressed as % of subjects; severity ¼ maximal intensity over 24-hour period.
the treatment groups showed that the cumulative dropout rate in the tibolone 2.5 and 5.0 mg groups was significantly less than in the placebo group ( P < 0.0001), whereas no significant differences between tibolone 0.625 mg, 1.25 mg and placebo were found. This lower percentage of total dropouts in the 2.5 and 5.0 mg groups was mainly the result of a lower number of dropouts due to insufficient therapeutic effect in these groups. A highly significant linear trend in dropout incidence due to insufficient therapeutic effect was observed (Table 2) (i.e. 14.6% in the placebo group, 9.0% in the tibolone 0.625 mg group, 9.5% in the tibolone 1.25 mg group, 1.9% in the tibolone 2.5 mg group and 1.3% in the tibolone 5.0 mg group; P < 0.0001). The incidence of discontinuations due to adverse experiences was similar in all treatment groups. Vaginal bleeding was not a major reason for discontinuation in this study; only two subjects, one in the tibolone 1.25 mg group and one in the tibolone 5.0 mg group, reported bleeding as reason for discontinuation.
Drug compliance was high, about 98% in all five treatment groups, as indicated by the diary cards and returned tablets. Climacteric symptoms at baseline are summarised in Table 1. Subjects that were randomised to the tibolone 0.625 mg and tibolone 1.25 mg groups had on average a somewhat higher number of hot flushes and sweating episodes compared with the other treatment groups. About 50% of all subjects had severe or very severe hot flushes and sweating episodes at baseline. For about 26% of the subjects, the flushes or sweating episodes interfered severely or very severely with daily life. The frequency of hot flushes and sweating episodes per treatment group during the 12-week study period is depicted in Figs 1 and 2, respectively. For both hot flushes and sweating episodes, a highly significant linear trend indicating a dose-related suppression of climacteric complaints by tibolone was observed after 12 weeks ( P < 0.0001). The tibolone 1.25, 2.5 and 5.0 mg groups were all
Table 2. Number of subjects per reason for discontinuation. All-Subjects-Treated group. Values are given as n (%). Reason for discontinuation
Placebo (n ¼ 151)
Tibolone 0.625 mg (n ¼ 155)
Insufficient therapeutic effect Unacceptable adverse experience or intercurrent illness Vaginal bleeding Other reasons Total number of dropouts
22 (14.6) 5 (3.3) 0 4 (2.6) 30 (19.9)
14 (9.0) 7 (4.5) 0 0 20 (12.9)
More than one reason per subject is possible.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
Tibolone 1.25 mg (n ¼ 148) 14 6 1 1 19
(9.5) (4.1) (0.7) (0.7) (12.8)
Tibolone 2.5 mg (n ¼ 158) 3 (1.9) 8 (5.1) 0 5 (3.2) 15 (9.5)
Tibolone 5.0 mg (n ¼ 158) 2 8 1 4 15
(1.3) (5.1) (0.7) (2.5) (9.5)
1112
M.B. LANDGREN ET AL.
Fig. 1. Frequency of hot flushes. The number of hot flushes per 24-hour period in the last week prior to each assessment was determined for subjects receiving either placebo (o), tibolone 0.625 mg (y), 1.25 mg (E), 2.5 mg (þ) or 5.0 mg (.). Results are expressed as mean numbers (per treatment group) for the All-Subjects-Evaluable group (unadjusted mean and standard error for baseline, ANCOVA least squares mean and standard error for post-baseline assessments). *P < 0.0125 is significant.
significantly more effective than placebo ( P < 0.0001), whereas the 0.625 mg dose was not significantly different from placebo. The effects of different doses of tibolone on the intensity of climacteric complaints were in accordance with the effects on the frequency; subjects in the tibolone 1.25, 2.5 or 5.0 mg groups had significantly less intense complaints than subjects in the placebo group ( P < 0.0001). After 12 weeks of treatment, the percentage of subjects in the tibolone 1.25, 2.5 or 5.0 mg groups having no or mild symptoms was about 86% compared with about 55% in the placebo or tibolone 0.625 mg group. Tibolone 0.625 mg was not different from placebo, regarding either frequency or intensity of hot flushes or sweating episodes. The proportion of responders in the treatment groups was defined as the percentage of subjects with a decrease from baseline of three or more hot flushes or sweats per day. Only subjects with three or more hot flushes or sweats at baseline were included in the analysis. The results are presented in Table 3. Regarding hot flushes, the proportion of ‘complete responders’ (subjects having no or at most one mild hot
Fig. 2. Frequency of sweating episodes. The number of sweating episodes per 24-hour period in the last week prior to each assessment was determined for subjects receiving either placebo (o), tibolone 0.625 mg (y), 1.25 mg (E), 2.5 mg (þ) or 5.0 mg (.). Results are expressed as mean numbers (per treatment group) for the All-Subjects-Evaluable group (unadjusted mean and standard error for baseline, ANCOVA least squares mean and standard error for post-baseline assessments). *P < 0.0125 is significant.
flush or sweating episode per day) was 28.6% in the placebo group, 27.9% in the tibolone 0.625 mg group, 51.2% in the 1.25 mg group, 62.9% in the 2.5 mg group and 76.6% in the 5.0 mg group. For sweating episodes, the percentages of ‘complete responders’ in the different groups were 33.6%, 37.5%, 55.8%, 64.3% and 74.5%, respectively. The ‘complete response’ rates in the tibolone 1.25, 2.5 and 5.0 mg groups were significantly higher than in the placebo group for both parameters ( P < 0.001). As can be seen in Figs 1 and 2, the reduction in the number of hot flushes and sweating episodes after eight weeks is very similar to the effect after 12 weeks. However, after four weeks of treatment, the number of hot flushes in the tibolone 1.25 mg group was not significantly different from placebo, whereas a significant difference was observed for the 2.5 and 5.0 mg groups, compared with placebo (Fig. 1). Furthermore, no statistically significant difference in ‘complete response’ rate (combined measure of frequency and intensity) was observed between tibolone 1.25 mg and placebo after four weeks, regarding either hot flushes
Table 3. Percentage of responders after 12 weeks (subjects with a decrease from baseline of three or more hot flushes or sweats per day). Values are given as n (%).
Hot flushes Sweats
Placebo
Tibolone 0.625 mg
Tibolone 1.25 mg
Tibolone 2.5 mg
Tibolone 5.0 mg
111 (55.0) 110 (57.3)
127 (66.9) 117 (67.5)
117 (82.1) 106 (80.2)
130 (87.7) 124 (83.9)
134 (92.5) 118 (91.5)
n ¼ number of subjects with three or more hot flushes or sweats per day at baseline.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
DOSE – RESPONSE STUDY WITH TIBOLONE
(22.9% for the tibolone 1.25 mg group versus 14.7% for the placebo group), or sweats (32.1% for the tibolone 1.25 mg group versus 21.0% for the placebo group). Analysis of possible factors that may have influenced the ‘complete response’ to tibolone revealed that there is a lower ‘complete response’ among older subjects (44% in subjects >50 years versus 53% in subjects 50 years) and among subjects that had used HRT in the past (42% in previous HRT users versus 55% in non-HRT users). An additional analysis was performed on a subgroup of subjects with at least seven hot flushes and sweating episodes per day (data not shown). Regarding the frequency and intensity of hot flushes and sweating episodes, the different doses of tibolone were as effective in this subgroup as in the total study population. Evaluation of vaginal bleeding events was based on the subjects’ diary cards. Incidences of bleeding and/or spotting in the different treatment groups at the four assessments are depicted in Fig. 3. A significant dose-related increase in the occurrence of vaginal bleeding and/or spotting was observed ( P < 0.0001). The placebo, tibolone 0.625 mg and tibolone 1.25 mg groups showed a comparable bleeding and/or spotting pattern, whereas in the tibolone 2.5 mg group a higher incidence was only observed in the first four weeks but not in the second and third months of treatment. In the tibolone 5.0 mg group, a higher bleeding and/or spotting incidence was observed throughout the whole study period. A total of 313 subjects from the All-Subjects-Treated group (40.6%) reported at least one adverse experience. Of these subjects, 167 (21.7%) reported at least one adverse experience that was considered possibly, probably or definitely related to the study medication, according to the investigator(s). No difference in incidences of drug-related adverse experiences for the placebo, tibolone 0.625, 1.25 and 2.5 mg group was observed, whereas about a twofold higher incidence was observed in the tibolone 5.0 mg group (data not shown). Eight subjects reported a serious adverse
Fig. 3. Incidence of vaginal bleeding and/or spotting throughout the study period. Incidence of vaginal bleeding and/or spotting as reported by subjects receiving either placebo (open bars), tibolone 0.625 mg (singlehatched bars), 1.25 mg (double-hatched bars), 2.5 mg (cross-hatched bars) or 5.0 mg (black bars) is depicted for the All-Subjects-Treated group with diary cards.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
1113
experience (SAE); commotio cerebri was reported by a subject in the placebo group; abdominal pain, deep venous thrombosis (possibly related to the study medication according to the investigator), commotio cerebri, headache and vertigo (possibly related to the study medication according to the investigator) were reported in the tibolone 0.625 mg group; retinal detachment in the 2.5 mg group; embolism and cholecystitis in the 5.0 mg group.
DISCUSSION In the present study, four different doses of tibolone, ranging from 0.625 to 5.0 mg per day, were compared with placebo with regard to climacteric symptoms, vaginal bleeding and acceptability. In order to determine the clinically optimal tibolone dose, efficacy was weighed against side effects for each dose. Primary efficacy parameters for climacteric symptoms were the frequency and intensity of hot flushes and sweating episodes. With regard to these parameters, tibolone at daily doses of 1.25, 2.5 and 5.0 mg was significantly more effective than placebo at 12 weeks, whereas tibolone at a daily dose of 0.625 mg was not different from placebo. Thus, the tibolone doses 1.25, 2.5 and 5.0 mg would be appropriate. The results of the 1.25 mg dose after four weeks suggest a slower onset of action, compared with the 2.5 and 5.0 mg doses. This slower onset of action, the lower percentage of ‘complete responders’ and the greater number of dropouts due to insufficient therapeutic effect indicate that tibolone 1.25 mg appears to be suboptimal, although clearly more effective than placebo. Hence, the preferred tibolone doses for treatment of climacteric symptoms are 2.5 and 5.0 mg. The absence of regular withdrawal bleedings differentiates tibolone treatment from conventional sequential oestrogen/progestogen therapy. However, bleeding or spotting is very common in postmenopausal women taking (continuous combined) HRT, especially in the first months of treatment10,11. For patient’s acceptance of (long term) treatment, it is important to achieve a low bleeding incidence, as vaginal bleedings after menopause are regarded as unacceptable by many women. The results from this study indicate a significant dose-related increase in the occurrence of vaginal bleeding. However, this vaginal bleeding was not regarded as unacceptable, as evidenced by the very low dropout rate for this reason (only one subject in the 1.25 mg and one subject in the 5.0 mg group reported vaginal bleeding as a major reason for discontinuation). Bleeding incidence on 5.0 mg tibolone is twice as high as on tibolone 2.5 mg in the present study, whereas bleeding incidences on 0.625, 1.25 and 2.5 mg are comparable. However, the bleeding incidence on 5.0 mg is not abnormally high; studies with continuous combined hormone replacement therapies (ccHRT) indicate that the incidence of vaginal bleeding with ccHRT regimens is comparable to
1114
M.B. LANDGREN ET AL.
tibolone 5.0 mg and is also not regarded as unacceptable by ccHRT users6,10. A high incidence of vaginal bleeding in patients receiving daily doses of 5.0 mg tibolone was supported by data from a smaller, placebo-controlled, clinical efficacy study (25 subjects) by Lindsay et al.12. Thus, with respect to bleeding, the preferred tibolone doses are 0.625, 1.25 and 2.5 mg. The incidence and nature of adverse experiences and the number of dropouts are an indication for the ‘acceptability’ of treatment for the various doses of tibolone. Both the total adverse experience incidence and the incidence of adverse experiences related to the study medication (as indicated by the investigator) were higher in the tibolone 5.0 mg dose group, compared with the other tibolone dose groups, which showed comparable incidences that were only slightly higher than in the placebo group. It is important to note that there is no difference in the incidence of adverse experiences/SAEs between the 2.5 and 1.25 mg dose group in this study. Dropout rate due to adverse experiences was low and not different between the treatment groups. Summarising, with regard to adverse experiences, the preferred tibolone doses are 0.625, 1.25 and 2.5 mg. In conclusion, whereas tibolone doses of 2.5 and 5.0 mg have a clinically adequate effect on hot flushes and sweating episodes, the 5.0 mg dose is less acceptable with regard to vaginal bleeding and other untoward effects. Hence, tibolone at a daily dose of 2.5 mg (Livial) is the optimal dose for treating climacteric symptoms, even in highly symptomatic subjects, offering the best balance between symptom relief, vaginal bleeding and adverse experiences.
Acknowledgements The following investigators and study centres participated in this multicentre study: (1) Vest-Agder Sentralsykehus, Kristiansand, Norway (Dr I Fjærestad); (2) Bergen, Norway (Dr T Løvset); (3) Fylkessjukehuset I Haugesund, Norway (Dr B Eriksen); (4) Sintef Unimed, Trondheim, Norway (Dr H Bratt); (5) Maria Hospital, Tilburg, the Netherlands (Dr JMWM Merkus); (6) Slotervaart Hospital, Amsterdam, the Netherlands (Dr A van Enk); (7) Sint Joseph Hospital, Veldhoven, the Netherlands (Dr JHJM Meuwissen); (8) Elisabeth Gasthuis, Arnhem, the Netherlands (Dr HAIM van Leusden); (9) Medisch Spectrum Twente, Enschede, the Netherlands (Dr HR Franke); (10) St Maartens Gasthuis, Venlo, the Netherlands (Dr HJ van Geuns); (11) Beatrix Ziekenhuis, Gorinchem, the Netherlands (Dr WBJ Funk); (12) Ziekenhuis Gelderse Vallei, Bennekom, the Netherlands (Dr GM Bouw); (13) Universitetssjukhuset, Umea, Sweden (Prof T Ba¨ckstro¨m); (14) Karolinska Sjukhuset, Stockholm, Sweden (Ass Prof BM Landgren); (15) Sjukhuset, Ha¨rno¨sand, Sweden (Dr T Fryklund); (16) La¨nssjukhuset
Ryhov, Jo¨nko¨ping, Sweden (Dr F Solheim); (17) Laserettet, Skelleftea˚ , Sweden (Dr R Schliker); (18) La¨ nsjukhuset, Kalmar, Sweden (Dr M Hurtig); (19) Huddinge Sjukhus, Huddinge, Sweden (Ass Prof A Jonasson); (20) Va¨rnamo Sjukhus, Va¨rnamo, Sweden (Dr C Gunnervik); (21) Gynmottagningen, Klippan, Sweden (Dr B Persson); (22) La¨a¨ka¨rikeskus Gyneko Oy, Oulu, Finland (Dr L Ma¨ka¨ra¨inen); (23) Tampereen La¨a¨ka¨rikeskus, Tampere, Finland (Prof R Punnonen); (24) Lahden Uro-Gyn, Lahti, Finland (Dr S Hulkko); (25) Turun Gynekologikeskus, Turku, Finland (Dr R Erkkola); (26) Laboratorio Gyne Oy, Kuopio, Finland (Dr M Makkonen); (27) La¨a¨ka¨riasema Femeda, Helsinki, Finland (Prof O Ylikorkala); (28) Gynekologinen La¨a¨ka¨riasema, Helsinki, Finland (Dr E Hirvonen).
References 1. Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem Mol Biol 2001;76:231 – 238. 2. Moore RA. Livial: a review of clinical studies. Br J Obstet Gynaecol 1999;106(Suppl 19):1 – 21. 3. Egarter C, Huber J, Leikermoser R, et al. Tibolone versus conjugated estrogens and sequential progestogen in the treatment of climacteric complaints. Maturitas 1996;23:55 – 62. 4. Siseles NO, Halperin H, Benencia HJ, et al. A comparative study of two hormone replacement therapy regimens on safety and efficacy variables. Maturitas 1995;21:201 – 210. 5. Crona N, Samsioe G, Lindberg U-B, Silfverstolpe G. Treatment of climacteric complaints with Org OD 14. Comparative study with oestradiol valerate and placebo. Maturitas 1988;9:303 – 308. 6. Hammar M, Christau S, Nathorst-Bo¨o¨s J, Rud T, Garre K. A doubleblind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynaecol 1998; 105:904 – 911. 7. Bjarnason NH, Bjarnason K, Haarbo J, Rosenquist C, Christiansen C. Tibolone: prevention of bone loss in late postmenopausal women. J Clin Endocrinol Metab 1996;81:2419 – 2422. 8. Berning B, Kuijk C van, Kuiper JW, Coelingh Bennink HJT, Kicovic PM, Fauser BCJM. Effects of two doses of tibolone on trabecular and cortical bone loss in early postmenopausal women: a twoyear randomized, placebo-controlled study. Bone 1996;19:395 – 399. 9. Gallagher JC, Baylink DJ, Freeman R, McClung M. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose finding studies. J Clin Endocrinol Metab 2001;86:4717 – 4726. 10. Archer DF, Pickar JH, Bottiglioni F for the Menopause Study Group. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994;83:686 – 692. 11. Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effect of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001;75:1080 – 1087. 12. Lindsay R, Hart DM, Kraszewski A. A prospective, double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis. BMJ 1980;280:1207 – 1209. Accepted 24 July 2002
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
Dose–response analysis of effects of tibolone on climacteric symptoms M.B. Landgrena, H.J.T. Coelingh Benninkb, F.A. Helmondc,*, S. Engelend Objective To assess the clinically optimal tibolone dose for the relief of climacteric complaints. Design A randomised, double blind, placebo-controlled trial. Setting Twenty-eight centres in Norway, The Netherlands, Sweden and Finland. Population Seven hundred and seventy-five healthy postmenopausal women were randomised to tibolone in a daily dose of 0.625, 1.25, 2.5 or 5.0 mg or placebo for 12 weeks. Methods At baseline, and after 4, 8 and 12 weeks, hot flushes, sweating, vaginal bleeding and adverse experiences were recorded. Main outcome measures Change in frequency and intensity of hot flushes and sweating over 12 weeks. Results From week four onwards, 2.5 and 5.0 mg tibolone were significantly more effective than placebo, regarding the frequency of hot flushes and sweating ( P < 0.001), whereas the 0.625 mg dose was not significantly different from placebo during the study. The frequency of hot flushes with the 1.25 mg dose was statistically significantly different from placebo, only from week eight onwards. The incidence of dropouts due to insufficient therapeutic effect was much higher in the tibolone 1.25 mg group (9.5%) than in the 2.5 (1.9%) and 5.0 mg (1.3%) groups. A dose-related increase in incidence of vaginal bleeding or spotting was observed ( P < 0.0001). Bleeding incidence in the 5.0 mg dose group was about twice as high as in the 2.5 mg dose group. There was no difference in incidence of adverse experiences between the 2.5- and the 1.25 mg dose group. Conclusion A daily dose of 2.5 mg tibolone is the clinically optimal dose for the treatment of climacteric complaints in postmenopausal women. INTRODUCTION Oestrogen replacement therapy has been shown to be effective in alleviating the often distressing features of the menopause, such as hot flushes and sweating. To prevent endometrium stimulation, oestrogen therapy has been combined with progestogens, which may introduce progestogen-related adverse experiences. An attractive approach to hormone replacement therapy (HRT) is offered by tibolone, a compound with tissue-specific effects1, mediated via steroid receptors and enzymatic pathways resulting in positive clinical effects on hot flushes and sweating, bone, vagina, and avoids stimulation of the endometrium.
Several placebo- and active-controlled studies have shown that tibolone in a daily dose of 2.5 mg (Livial) alleviates climacteric complaints such as hot flushes and sweating episodes2, its activity being comparable to that of 0.625 mg conjugated oestrogens3,4 or 2 mg oestradiol5,6. Thus far, only limited published data on the efficacy of other doses of tibolone are available. It has been suggested that doses of tibolone lower than the current marketed formulation might be beneficial for the prevention of bone loss7 – 9. The aim of the present study was to assess the clinically optimal dose of tibolone for HRT in postmenopausal women.
METHODS a
Karolinska Hospital, Stockholm, Sweden b Program Management Section, NV Organon, Oss, The Netherlands c Clinical Development Department, NV Organon, Oss, The Netherlands d Clinical Trials Operations Biometrics, NV Organon, Oss, The Netherlands * Correspondence: Dr F. A. Helmond, International Marketing, KA 4016, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands. D RCOG 2002 BJOG: an International Journal of Obstetrics and Gynaecology PII: S 1 4 7 0 - 0 3 2 8 ( 0 2 ) 0 2 9 2 0 - 8
The study was designed as a multicentre, randomised, double blind, placebo-controlled, dose –response study in postmenopausal women who experience hot flushes and sweating episodes. The study was conducted in 28 centres, located in Sweden (n ¼ 9), the Netherlands (n ¼ 8), Finland (n ¼ 7) and Norway (n ¼ 4). The study was performed between March 1994 and July 1995 and was in full compliance with the Declaration of Helsinki, plus revisions. The study protocol was approved by the ethics committee for each centre, and all subjects had www.bjog-elsevier.com
1110
M.B. LANDGREN ET AL.
given written informed consent before participation in the study. Subjects were selected according to a number of criteria. Included were non-hysterectomised women between 40 and 60 years, with absence of spontaneous vaginal bleeding for at least 10 months and presence of climacteric symptoms (at least one moderate to severe hot flush per day). Body weight had to be between 80% and 130% of the ideal body weight (Metropolitan Life Insurance Company Tables for Women). Women with the following conditions were excluded: history or presence of any malignant disorder, cardiovascular or cerebrovascular disease, thromboembolism/thrombosis, hepatic or renal disease, epilepsy or classical migraine, vaginal bleeding of unknown aetiology, hypertension (systolic BP > 170 mmHg and/or diastolic BP > 105 mmHg), rheumatoid arthritis, diabetes mellitus, hyperlipidaemia (fasting cholesterol > 8.5 mmol/L and/or fasting triglycerides > 2.5 mmol/L), any serious disease or psychiatric disorder, hypersensitivity to oestrogen and/or progestogen, disease for which exogenous hormonal steroids are contraindicated. The use of sex steroids within six weeks, or ethinyloestradiol within the last six months, or hormone implants at any time previously, one or more of the following drugs during the last two months: hydantoins, barbiturates, primidone, carbamazepine, rifampicine, griseofulvin, drugs for the treatment of climacteric symptoms (excluding homeopathic drugs); alcohol abuse and/or drug abuse within the last 12 months and smoking more than 10 cigarettes per day was also a reason for exclusion. After written informed consent was obtained, subjects underwent a general and a gynaecologic examination. Concomitant cholesterol lowering treatment and starting homeopathic drugs during the treatment were not allowed. Study medication was tibolone (oral tablets; NV Organon, Oss, the Netherlands) in a daily dose of 0.625, 1.25, 2.5 (Livial) or 5 mg, or placebo (oral tablets that were identical in appearance). Eligible subjects were numbered consecutively per centre, and received the corresponding treatment number from the randomisation list. Tablet intake and occurrence of vaginal bleeding were recorded in a diary booklet. At baseline, after 4, 8, and 12 weeks, climacteric symptoms were recorded. Frequency of climacteric symptoms was expressed as an average number per 24-hour period in the last week before each assessment. Intensity of climacteric symptoms was scored by the subjects on a five-step self-rating scale adapted from the climacteric symptoms rating scale developed by Collins and Landgren (Karolinska Hospital, Stockholm, Sweden). A combined measure of frequency and intensity of the symptoms was obtained by defining a ‘complete responder’ as a subject having no or at most one mild hot flush or sweating episode per day. In addition, after 12 weeks, a general and gynaecologic examination was performed. The vaginal bleeding pattern (spotting and/or bleeding) and number and nature of adverse experiences were recorded throughout the study period.
The clinically optimal dose was determined by weighing efficacy against side effects. The primary objective was to assess the reduction in the frequency and intensity of hot flushes and sweating episodes achieved by four different doses of tibolone compared with placebo. The secondary objective was to obtain dose – response related data on vaginal bleeding. A sample size of 5 80 evaluable subjects was planned in order to be able to detect a difference of 25% in response rates between placebo and a dose group, with a power of 80% at a significance level of 1.25% (m2 test, with Bonferoni correction for multiple comparisons). A total of 775 (5 155) subjects were recruited to compensate for expected dropouts and non-evaluable subjects. The number of hot flushes and sweating episodes was analysed by non-parametric Cochran – Mantel – Haenszel (CMH) tests, adjusted for centre, for overall and pairwise group differences (dose group versus placebo), using modified ridit scores. The Bonferoni correction for multiple testing was applied to the four pairwise comparisons (i.e. a significance level of 0.0125 was used for each of the four pairwise comparisons). In addition, analysis of covariance, with baseline as covariable, and adjustment of extreme outliers was performed in order to give estimates of treatment differences. Linear trend tests for the doserelated trend were performed using the Mantel – Haenszel m2 test with 1 df based on the equally spaced treatment groups (scores 0, 1, 2, 3, 4 for the respective dose groups). Proportional odds regression analysis was applied to the intensity of hot flushes and sweating episodes. CMH tests were also applied to response rates and occurrence of vaginal bleeding. Comparison between a dose group and placebo with respect to cumulative dropout rates was performed by log-rank tests using Kaplan – Meier estimates. Explorative analyses were performed on response rates using stepwise linear logistic regression to investigate the effects of potential prognostic factors such as age, time since menopause and previous use of HRT.
RESULTS A total of 775 subjects were randomised across the five treatment groups. Five subjects did not start treatment, so the All-Subjects-Treated group consisted of 770 subjects. In total, 740 subjects were evaluable for the All-SubjectsEvaluable group (all treated subjects with at least one postbaseline assessment). Demographic data for this group are presented in Table 1. No differences between the five treatment groups were observed. Of the All-Subjects-Treated group, 99 subjects (12.9%) discontinued. An overview of the number of dropouts per treatment group and reason for discontinuation is given in Table 2. The most frequently reported reasons were insufficient therapeutic effect (55 subjects) and adverse experience-related reasons (36 subjects). Pairwise comparison of D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
DOSE – RESPONSE STUDY WITH TIBOLONE
1111
Table 1. Demographic data and climacteric symptoms at baseline [mean (SD)] for the All-Subjects-Evaluable group. Placebo (n ¼ 143)
Tibolone 0.625 mg (n ¼ 149)
Age (years) [range] 52.9 (3.5) [43 – 60] 52.2 (3.5) Height (cm) 164.2 (6.4) 165.7 Body weight (kg) 67.5 (8.4) 67.2 25.0 (2.6) 24.5 Body mass index (kg/m2) Time since menopause (months) [range] 37.3 (19.9) [0 – 116] 34.1 (18.9) Number of hot flushesa Intensity of hot flushesb None Mild Moderate Severe Very severe Number of sweating episodesa Intensity of sweating episodesb None Mild Moderate Severe Very severe a b
8.1 (4.8)
Tibolone 1.25 mg (n ¼ 143)
2.7 4.7 42.3 37.6 12.8
7.5 (4.9)
9.2 (5.7)
8.2 (5.6)
1.4 3.5 40.6 45.5 9.1
9.9 (17.0)
3.5 9.8 33.6 41.3 11.9
Tibolone 5.0 mg (n ¼ 151)
[40 – 60] 51.6 (3.5) [42 – 58] 51.8 (3.4) [42 – 59] 52.5 (3.2) [43 – 60] (5.9) 164.5 (5.3) 164.8 (5.7) 164.9 (5.9) (8.5) 67.3 (8.9) 67.7 (9.3) 67.7 (9.3) (2.7) 24.8 (2.9) 24.9 (3.0) 24.9 (3.1) [12 – 130] 33.3 (21.4) [6 – 200] 34.0 (21.5) [2 – 214] 35.1 (19.6) [1 – 116]
9.8 (6.6)
1.4 4.2 43.4 40.6 10.5
Tibolone 2.5 mg (n ¼ 154)
4.7 9.4 35.6 38.9 11.4
0.6 6.5 38.3 43.5 11.0
8.1 (5.7)
7.5 (6.2)
4.9 7.0 36.4 41.3 10.5
4.5 10.4 35.7 42.2 7.1
8.2 (5.3)
0 4.0 33.8 47.0 15.2 7.0 (5.2)
4.6 7.3 32.5 41.1 14.6
Defined as total number per 24-hour period; mean (SD). Expressed as % of subjects; severity ¼ maximal intensity over 24-hour period.
the treatment groups showed that the cumulative dropout rate in the tibolone 2.5 and 5.0 mg groups was significantly less than in the placebo group ( P < 0.0001), whereas no significant differences between tibolone 0.625 mg, 1.25 mg and placebo were found. This lower percentage of total dropouts in the 2.5 and 5.0 mg groups was mainly the result of a lower number of dropouts due to insufficient therapeutic effect in these groups. A highly significant linear trend in dropout incidence due to insufficient therapeutic effect was observed (Table 2) (i.e. 14.6% in the placebo group, 9.0% in the tibolone 0.625 mg group, 9.5% in the tibolone 1.25 mg group, 1.9% in the tibolone 2.5 mg group and 1.3% in the tibolone 5.0 mg group; P < 0.0001). The incidence of discontinuations due to adverse experiences was similar in all treatment groups. Vaginal bleeding was not a major reason for discontinuation in this study; only two subjects, one in the tibolone 1.25 mg group and one in the tibolone 5.0 mg group, reported bleeding as reason for discontinuation.
Drug compliance was high, about 98% in all five treatment groups, as indicated by the diary cards and returned tablets. Climacteric symptoms at baseline are summarised in Table 1. Subjects that were randomised to the tibolone 0.625 mg and tibolone 1.25 mg groups had on average a somewhat higher number of hot flushes and sweating episodes compared with the other treatment groups. About 50% of all subjects had severe or very severe hot flushes and sweating episodes at baseline. For about 26% of the subjects, the flushes or sweating episodes interfered severely or very severely with daily life. The frequency of hot flushes and sweating episodes per treatment group during the 12-week study period is depicted in Figs 1 and 2, respectively. For both hot flushes and sweating episodes, a highly significant linear trend indicating a dose-related suppression of climacteric complaints by tibolone was observed after 12 weeks ( P < 0.0001). The tibolone 1.25, 2.5 and 5.0 mg groups were all
Table 2. Number of subjects per reason for discontinuation. All-Subjects-Treated group. Values are given as n (%). Reason for discontinuation
Placebo (n ¼ 151)
Tibolone 0.625 mg (n ¼ 155)
Insufficient therapeutic effect Unacceptable adverse experience or intercurrent illness Vaginal bleeding Other reasons Total number of dropouts
22 (14.6) 5 (3.3) 0 4 (2.6) 30 (19.9)
14 (9.0) 7 (4.5) 0 0 20 (12.9)
More than one reason per subject is possible.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
Tibolone 1.25 mg (n ¼ 148) 14 6 1 1 19
(9.5) (4.1) (0.7) (0.7) (12.8)
Tibolone 2.5 mg (n ¼ 158) 3 (1.9) 8 (5.1) 0 5 (3.2) 15 (9.5)
Tibolone 5.0 mg (n ¼ 158) 2 8 1 4 15
(1.3) (5.1) (0.7) (2.5) (9.5)
1112
M.B. LANDGREN ET AL.
Fig. 1. Frequency of hot flushes. The number of hot flushes per 24-hour period in the last week prior to each assessment was determined for subjects receiving either placebo (o), tibolone 0.625 mg (y), 1.25 mg (E), 2.5 mg (þ) or 5.0 mg (.). Results are expressed as mean numbers (per treatment group) for the All-Subjects-Evaluable group (unadjusted mean and standard error for baseline, ANCOVA least squares mean and standard error for post-baseline assessments). *P < 0.0125 is significant.
significantly more effective than placebo ( P < 0.0001), whereas the 0.625 mg dose was not significantly different from placebo. The effects of different doses of tibolone on the intensity of climacteric complaints were in accordance with the effects on the frequency; subjects in the tibolone 1.25, 2.5 or 5.0 mg groups had significantly less intense complaints than subjects in the placebo group ( P < 0.0001). After 12 weeks of treatment, the percentage of subjects in the tibolone 1.25, 2.5 or 5.0 mg groups having no or mild symptoms was about 86% compared with about 55% in the placebo or tibolone 0.625 mg group. Tibolone 0.625 mg was not different from placebo, regarding either frequency or intensity of hot flushes or sweating episodes. The proportion of responders in the treatment groups was defined as the percentage of subjects with a decrease from baseline of three or more hot flushes or sweats per day. Only subjects with three or more hot flushes or sweats at baseline were included in the analysis. The results are presented in Table 3. Regarding hot flushes, the proportion of ‘complete responders’ (subjects having no or at most one mild hot
Fig. 2. Frequency of sweating episodes. The number of sweating episodes per 24-hour period in the last week prior to each assessment was determined for subjects receiving either placebo (o), tibolone 0.625 mg (y), 1.25 mg (E), 2.5 mg (þ) or 5.0 mg (.). Results are expressed as mean numbers (per treatment group) for the All-Subjects-Evaluable group (unadjusted mean and standard error for baseline, ANCOVA least squares mean and standard error for post-baseline assessments). *P < 0.0125 is significant.
flush or sweating episode per day) was 28.6% in the placebo group, 27.9% in the tibolone 0.625 mg group, 51.2% in the 1.25 mg group, 62.9% in the 2.5 mg group and 76.6% in the 5.0 mg group. For sweating episodes, the percentages of ‘complete responders’ in the different groups were 33.6%, 37.5%, 55.8%, 64.3% and 74.5%, respectively. The ‘complete response’ rates in the tibolone 1.25, 2.5 and 5.0 mg groups were significantly higher than in the placebo group for both parameters ( P < 0.001). As can be seen in Figs 1 and 2, the reduction in the number of hot flushes and sweating episodes after eight weeks is very similar to the effect after 12 weeks. However, after four weeks of treatment, the number of hot flushes in the tibolone 1.25 mg group was not significantly different from placebo, whereas a significant difference was observed for the 2.5 and 5.0 mg groups, compared with placebo (Fig. 1). Furthermore, no statistically significant difference in ‘complete response’ rate (combined measure of frequency and intensity) was observed between tibolone 1.25 mg and placebo after four weeks, regarding either hot flushes
Table 3. Percentage of responders after 12 weeks (subjects with a decrease from baseline of three or more hot flushes or sweats per day). Values are given as n (%).
Hot flushes Sweats
Placebo
Tibolone 0.625 mg
Tibolone 1.25 mg
Tibolone 2.5 mg
Tibolone 5.0 mg
111 (55.0) 110 (57.3)
127 (66.9) 117 (67.5)
117 (82.1) 106 (80.2)
130 (87.7) 124 (83.9)
134 (92.5) 118 (91.5)
n ¼ number of subjects with three or more hot flushes or sweats per day at baseline.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
DOSE – RESPONSE STUDY WITH TIBOLONE
(22.9% for the tibolone 1.25 mg group versus 14.7% for the placebo group), or sweats (32.1% for the tibolone 1.25 mg group versus 21.0% for the placebo group). Analysis of possible factors that may have influenced the ‘complete response’ to tibolone revealed that there is a lower ‘complete response’ among older subjects (44% in subjects >50 years versus 53% in subjects 50 years) and among subjects that had used HRT in the past (42% in previous HRT users versus 55% in non-HRT users). An additional analysis was performed on a subgroup of subjects with at least seven hot flushes and sweating episodes per day (data not shown). Regarding the frequency and intensity of hot flushes and sweating episodes, the different doses of tibolone were as effective in this subgroup as in the total study population. Evaluation of vaginal bleeding events was based on the subjects’ diary cards. Incidences of bleeding and/or spotting in the different treatment groups at the four assessments are depicted in Fig. 3. A significant dose-related increase in the occurrence of vaginal bleeding and/or spotting was observed ( P < 0.0001). The placebo, tibolone 0.625 mg and tibolone 1.25 mg groups showed a comparable bleeding and/or spotting pattern, whereas in the tibolone 2.5 mg group a higher incidence was only observed in the first four weeks but not in the second and third months of treatment. In the tibolone 5.0 mg group, a higher bleeding and/or spotting incidence was observed throughout the whole study period. A total of 313 subjects from the All-Subjects-Treated group (40.6%) reported at least one adverse experience. Of these subjects, 167 (21.7%) reported at least one adverse experience that was considered possibly, probably or definitely related to the study medication, according to the investigator(s). No difference in incidences of drug-related adverse experiences for the placebo, tibolone 0.625, 1.25 and 2.5 mg group was observed, whereas about a twofold higher incidence was observed in the tibolone 5.0 mg group (data not shown). Eight subjects reported a serious adverse
Fig. 3. Incidence of vaginal bleeding and/or spotting throughout the study period. Incidence of vaginal bleeding and/or spotting as reported by subjects receiving either placebo (open bars), tibolone 0.625 mg (singlehatched bars), 1.25 mg (double-hatched bars), 2.5 mg (cross-hatched bars) or 5.0 mg (black bars) is depicted for the All-Subjects-Treated group with diary cards.
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114
1113
experience (SAE); commotio cerebri was reported by a subject in the placebo group; abdominal pain, deep venous thrombosis (possibly related to the study medication according to the investigator), commotio cerebri, headache and vertigo (possibly related to the study medication according to the investigator) were reported in the tibolone 0.625 mg group; retinal detachment in the 2.5 mg group; embolism and cholecystitis in the 5.0 mg group.
DISCUSSION In the present study, four different doses of tibolone, ranging from 0.625 to 5.0 mg per day, were compared with placebo with regard to climacteric symptoms, vaginal bleeding and acceptability. In order to determine the clinically optimal tibolone dose, efficacy was weighed against side effects for each dose. Primary efficacy parameters for climacteric symptoms were the frequency and intensity of hot flushes and sweating episodes. With regard to these parameters, tibolone at daily doses of 1.25, 2.5 and 5.0 mg was significantly more effective than placebo at 12 weeks, whereas tibolone at a daily dose of 0.625 mg was not different from placebo. Thus, the tibolone doses 1.25, 2.5 and 5.0 mg would be appropriate. The results of the 1.25 mg dose after four weeks suggest a slower onset of action, compared with the 2.5 and 5.0 mg doses. This slower onset of action, the lower percentage of ‘complete responders’ and the greater number of dropouts due to insufficient therapeutic effect indicate that tibolone 1.25 mg appears to be suboptimal, although clearly more effective than placebo. Hence, the preferred tibolone doses for treatment of climacteric symptoms are 2.5 and 5.0 mg. The absence of regular withdrawal bleedings differentiates tibolone treatment from conventional sequential oestrogen/progestogen therapy. However, bleeding or spotting is very common in postmenopausal women taking (continuous combined) HRT, especially in the first months of treatment10,11. For patient’s acceptance of (long term) treatment, it is important to achieve a low bleeding incidence, as vaginal bleedings after menopause are regarded as unacceptable by many women. The results from this study indicate a significant dose-related increase in the occurrence of vaginal bleeding. However, this vaginal bleeding was not regarded as unacceptable, as evidenced by the very low dropout rate for this reason (only one subject in the 1.25 mg and one subject in the 5.0 mg group reported vaginal bleeding as a major reason for discontinuation). Bleeding incidence on 5.0 mg tibolone is twice as high as on tibolone 2.5 mg in the present study, whereas bleeding incidences on 0.625, 1.25 and 2.5 mg are comparable. However, the bleeding incidence on 5.0 mg is not abnormally high; studies with continuous combined hormone replacement therapies (ccHRT) indicate that the incidence of vaginal bleeding with ccHRT regimens is comparable to
1114
M.B. LANDGREN ET AL.
tibolone 5.0 mg and is also not regarded as unacceptable by ccHRT users6,10. A high incidence of vaginal bleeding in patients receiving daily doses of 5.0 mg tibolone was supported by data from a smaller, placebo-controlled, clinical efficacy study (25 subjects) by Lindsay et al.12. Thus, with respect to bleeding, the preferred tibolone doses are 0.625, 1.25 and 2.5 mg. The incidence and nature of adverse experiences and the number of dropouts are an indication for the ‘acceptability’ of treatment for the various doses of tibolone. Both the total adverse experience incidence and the incidence of adverse experiences related to the study medication (as indicated by the investigator) were higher in the tibolone 5.0 mg dose group, compared with the other tibolone dose groups, which showed comparable incidences that were only slightly higher than in the placebo group. It is important to note that there is no difference in the incidence of adverse experiences/SAEs between the 2.5 and 1.25 mg dose group in this study. Dropout rate due to adverse experiences was low and not different between the treatment groups. Summarising, with regard to adverse experiences, the preferred tibolone doses are 0.625, 1.25 and 2.5 mg. In conclusion, whereas tibolone doses of 2.5 and 5.0 mg have a clinically adequate effect on hot flushes and sweating episodes, the 5.0 mg dose is less acceptable with regard to vaginal bleeding and other untoward effects. Hence, tibolone at a daily dose of 2.5 mg (Livial) is the optimal dose for treating climacteric symptoms, even in highly symptomatic subjects, offering the best balance between symptom relief, vaginal bleeding and adverse experiences.
Acknowledgements The following investigators and study centres participated in this multicentre study: (1) Vest-Agder Sentralsykehus, Kristiansand, Norway (Dr I Fjærestad); (2) Bergen, Norway (Dr T Løvset); (3) Fylkessjukehuset I Haugesund, Norway (Dr B Eriksen); (4) Sintef Unimed, Trondheim, Norway (Dr H Bratt); (5) Maria Hospital, Tilburg, the Netherlands (Dr JMWM Merkus); (6) Slotervaart Hospital, Amsterdam, the Netherlands (Dr A van Enk); (7) Sint Joseph Hospital, Veldhoven, the Netherlands (Dr JHJM Meuwissen); (8) Elisabeth Gasthuis, Arnhem, the Netherlands (Dr HAIM van Leusden); (9) Medisch Spectrum Twente, Enschede, the Netherlands (Dr HR Franke); (10) St Maartens Gasthuis, Venlo, the Netherlands (Dr HJ van Geuns); (11) Beatrix Ziekenhuis, Gorinchem, the Netherlands (Dr WBJ Funk); (12) Ziekenhuis Gelderse Vallei, Bennekom, the Netherlands (Dr GM Bouw); (13) Universitetssjukhuset, Umea, Sweden (Prof T Ba¨ckstro¨m); (14) Karolinska Sjukhuset, Stockholm, Sweden (Ass Prof BM Landgren); (15) Sjukhuset, Ha¨rno¨sand, Sweden (Dr T Fryklund); (16) La¨nssjukhuset
Ryhov, Jo¨nko¨ping, Sweden (Dr F Solheim); (17) Laserettet, Skelleftea˚ , Sweden (Dr R Schliker); (18) La¨ nsjukhuset, Kalmar, Sweden (Dr M Hurtig); (19) Huddinge Sjukhus, Huddinge, Sweden (Ass Prof A Jonasson); (20) Va¨rnamo Sjukhus, Va¨rnamo, Sweden (Dr C Gunnervik); (21) Gynmottagningen, Klippan, Sweden (Dr B Persson); (22) La¨a¨ka¨rikeskus Gyneko Oy, Oulu, Finland (Dr L Ma¨ka¨ra¨inen); (23) Tampereen La¨a¨ka¨rikeskus, Tampere, Finland (Prof R Punnonen); (24) Lahden Uro-Gyn, Lahti, Finland (Dr S Hulkko); (25) Turun Gynekologikeskus, Turku, Finland (Dr R Erkkola); (26) Laboratorio Gyne Oy, Kuopio, Finland (Dr M Makkonen); (27) La¨a¨ka¨riasema Femeda, Helsinki, Finland (Prof O Ylikorkala); (28) Gynekologinen La¨a¨ka¨riasema, Helsinki, Finland (Dr E Hirvonen).
References 1. Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem Mol Biol 2001;76:231 – 238. 2. Moore RA. Livial: a review of clinical studies. Br J Obstet Gynaecol 1999;106(Suppl 19):1 – 21. 3. Egarter C, Huber J, Leikermoser R, et al. Tibolone versus conjugated estrogens and sequential progestogen in the treatment of climacteric complaints. Maturitas 1996;23:55 – 62. 4. Siseles NO, Halperin H, Benencia HJ, et al. A comparative study of two hormone replacement therapy regimens on safety and efficacy variables. Maturitas 1995;21:201 – 210. 5. Crona N, Samsioe G, Lindberg U-B, Silfverstolpe G. Treatment of climacteric complaints with Org OD 14. Comparative study with oestradiol valerate and placebo. Maturitas 1988;9:303 – 308. 6. Hammar M, Christau S, Nathorst-Bo¨o¨s J, Rud T, Garre K. A doubleblind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynaecol 1998; 105:904 – 911. 7. Bjarnason NH, Bjarnason K, Haarbo J, Rosenquist C, Christiansen C. Tibolone: prevention of bone loss in late postmenopausal women. J Clin Endocrinol Metab 1996;81:2419 – 2422. 8. Berning B, Kuijk C van, Kuiper JW, Coelingh Bennink HJT, Kicovic PM, Fauser BCJM. Effects of two doses of tibolone on trabecular and cortical bone loss in early postmenopausal women: a twoyear randomized, placebo-controlled study. Bone 1996;19:395 – 399. 9. Gallagher JC, Baylink DJ, Freeman R, McClung M. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose finding studies. J Clin Endocrinol Metab 2001;86:4717 – 4726. 10. Archer DF, Pickar JH, Bottiglioni F for the Menopause Study Group. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994;83:686 – 692. 11. Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effect of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001;75:1080 – 1087. 12. Lindsay R, Hart DM, Kraszewski A. A prospective, double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis. BMJ 1980;280:1207 – 1209. Accepted 24 July 2002
D RCOG 2002 Br J Obstet Gynaecol 109, pp. 1109 – 1114