ORGINAL ARTICLE

Phase I11 clinical trial with a new oral contraceptive containing 150 pg desogestrel and 20 pg ethinylestradiol PAULLAMMERS AND MONIQUE OP TEN BERG From the Medical Services & Product Surveillance Department Organon International BV, Oss, The Netherlands

Acta Obstet Cynecol Scand 1991; 70: 497-500.

Results are presented of a Phase I11 international multicentre trial to study the effect of a new low-dose oral contraceptive (OC) containing 20 pg ethinylestradiol and 150 pg desogestrel (Mercilon@) regarding efficacy, cycle control, blood pressure, and acceptability. Altogether 1.684 women from 12 European countries were included in the study. Four pregnancies occurred, 3 of them patient failures, one tablet failure. The overall Pearl Index was 0.20. The frequency of irregular bleeding was comparable to that recorded with other commonly used low-dose OCs. No serious side effects occurred. The incidence of the most frequently reported subjective side effects -headache, nausea and breast tension -was already low after the first cycle of treatment and decreased to below pretreatment levels with continued use. There was a small increase in mean body weight, which was confined essentially to young women. The preparation did not affect the mean systolic or diastolic blood pressure. This new preparation has thus proved to be an effective, safe and well-accepted ultra low-dose oral contraceptive. Key words: low-dose oral contraceptive; efficacy; safety; multicenter study; desogestrel Submitted September 17, 1990 Accepted June I.?, 1991

Oral contraceptives (OCs) have been modified considerably over the almost 30 years they have been in use. Thanks to epidemiological research into the incidence of the thromboembolic side effects of OC use (1-4), the dose of estrogen in combined OCs has been reduced from 150 pg per tablet used in the early 1960s to the 30 pg dose in most currently available preparations. Other epidemiological studies have demonstrated a relationship between the risk of ischemic heart disease and the concentration of lipoproteins in serum (5-6). This has led to the development of a new generation of highly selective progestagens, of which desogestrel is the first and most commonly used. The availability of these progestogens raised hopes of

further reducing the estrogen dose in combined OC preparations. A new monophasic formulation of 20 pg ethinylestradiol (EE) plus 150 pg desogestrel was consequently developed. The results of an international multicentre phase 111 trial to assess the reliability, cycle control, side effects and effects on blood pressure and body weight of this new combination are reported here. The study was conducted at seventy-two centres in 12 European countries - Belgium, Denmark, Finland, France, Hungary, The Netherlands, Norway, Poland, Sweden, Switzerland, West Germany and Yugoslavia - all using the same protocol. The length of the study differed at some of the centres. Acla Obslei Gynecol Scand 70 (1991)

498

P. Lammers and M . op ten Berg

Table I. Age and cycle distribution

Age (yrs) t20 20-24 25-29 30-34 35 - 39 >39

Number

YO

Cycle

387 527 334 230 137 69

23.0 31.3 19.8 13.7 8.1 4.1

1 3 6

1681* 1531 I307

12 24 36

971 382 209

n

* Data on first three treatment cycles not available.

A total of 1,684 sexually active, healthy women were accepted into the study. Their age distribution is given in Table I. All the women were treated with the monophasic 20 pg/150 pg ethinylestradioVdesogestrel combined oral contraceptive Mercilon. The preparation was administered orally in a 28-day-cycle regimen, 3 weeks on medication followed by I week off. Each woman was provided with a calendar, on which she was instructed to record tablet-taking days as well as bleeding episodes. The latter were subdivided into bleeding, i.e. any bleeding requiring more than one sanitary towel per day, and spotting, i.e. a scanty bleeding requiring no or one sanitary towel per day. Bleeding cards were reviewed at each return visit, just as the occurrence of side effects was recorded and blood pressure and body weight were measured. In the analysis the following definitions were used for cycle control assessment:

* withdrawal bleeding: a vaginal bleeding starting in the tablet-free interval;

* irregular bleeding: any vaginal bleeding starting during the tablet-taking period; this was further subdivided into spotting and breakthrough bleeding, using the same criteria as for spotting and bleeding on the diary cards.

Of all enrolled women, 54.8% were ‘pill starters’, i.e. women who had not used oral contraception before or whose previous treatment had ended more Table 11. Characteristics of withdrawal bleeding (WTB) (“/o of women)

I 3 6

Regular WTB

87.8 90.3 92.9

Start of WTB on day 22-25

Duration of WTB t 5 days

Amount of WTB light or moderate

94.1 93.9 94.7

87.9 92.6 92.9

96.9 98.4 98,7

Actu Ohstet Gynecol Scund 70 (1991)

Results Cycle distribution is represented in Table I. Taken together, data on 25,970 cycles were obtained.

Reliability

Material and methods

Cycle

than 2 months before the start of the study. 40.2% were ‘switchers’ from other combined OC and 5.0% from progestogen-only pills. Unless specified differently, all data from the three groups are presented together.

Four pregnancies occurred during this study. Only one was considered to be a tablet failure, as all the tablets in this cycle were reported to be taken. The pregnancy rate for tablet failure was 0.05, the total pregnancy rate 0.20, including the 3 pregnancies due to patient failure (2,3, and 3 consecutive tablets were forgotten by these women respectively). In 1,362 cycles (5.2%), one or more tablets were missed.

Cycle control Table II lists certain characteristics of the withdrawal bleeding during use of the preparation. 87.8% of the women experienced a regular withdrawal bleeding in the first cycle, increasing with continued use. The duration and amount of withdrawal bleeding during use of the preparation, and in comparison with pretreatment menstrual bleeding, are shown in Tables I1 and I11 respectively. In approximately 94% of the cycles the withdrawal bleeding started 1 4 days after intake of the last tablet on the strip and lasted on average for 3-5 days in 83.6% of the women. Both duration and amount of withdrawal bleeding tended to decrease during use of the OC, as compared with pre-treatment. The incidence of irregular bleeding is shown in Table IV. The experience with this preparation paralleled that with other combination OCs in that incidence of spotting a n d o r breakthrough bleeding (BTB) was highest in the first cycle (spotting l8.2%, BTB 8.2%) and then rapidly tapered off until a stable level was reached within a few months. Discontinuation rates for bleeding irregularities were 1.8%, 3.0% and 5.2% after 3, 6 and 12 months respectively.

Side effects No cases of deep venous thrombosis occurred during use of the 20 pg EE-containing oral contraceptive. No other serious side effects were reported. Four cases of superficial thrombophlebitis were reported.

EEldesogestrel and contraceptive trial

499

Table 111. Duration and amount of withdrawal bleeding compared with pre-treatment menstrual bleeding (YOof women) Cycle

n

Total 1 3 6 Pill-starters 1 3 6

I

-

T

I

-

t

1476 1382 1214

46.4 51.4 52.2

34.3 33.5 31.6

19.3 15.1 16.2

23.6 26.8 30.1

71.7 69.2 65.4

4.7 4.1 4.4

79 1 751 647

52.7 60.4 58.9

30.2 28.1 28.7

17.1 11.5 12.4

27.4 30.9 35.4

69.4 66.8 62.4

3.2 2.3 2.2

41.3 41.2 35.3

22.6 20.4 21.7

19.2 22.5 24.3

74.2 71.2 68.6

6.5 6.3 7.1

Pill-switchers (from other combined OCs) 1 613 36. I 3 573 38.4 6 519 43.0

* T increase;

=

Amount *

Duration*

no change;

4 decrease.

The condition resolved upon treatment; 2 women continued with the preparation, the other 2 stopped. Table V reports the incidence of the relevant subjective side effects of OC use: nausea, breast tension, and headache, are shown for OC ‘starters’ and ‘switchers’ together, and for each group separately. As with all other low-dose combined preparations, there i s an initial increase in the incidence of nausea and headache in the first cycle in the pill-starters, which soon diminished to values actually below pretreatment values. In the group of ‘switchers’ from other combined OCs, there was a decrease in the incidence of the above-mentioned subjective side effects from the first cycle onwards. The discontinuation rate for subjective side effects was 8.0% after 24 cycles. The effect on body weight recorded during the trial was essentially an effect of natural growth: in young women < 1 9 years of age, average bodyweight increased from 55.12 kg at baseline to 55.50 kg after 12 cycles. In women from 20 to 29 years of age, average bodyweight remained the same (56.80 kg at baseline, 56.81 kg at cycle 12). The preparation did not affect the mean systolic or diastolic blood pressure (Table VI). Only 5 women dropped out because of a concurrent hypertension.

Discussion The monophasic oral contraceptive combination of 20 pg EE and 1.50 pg desogestrel was designed to reduce the estrogen dose while maintaining efficacy, safety, and acceptability. Use of this preparation through 25,970 cycles in 12 European countries resulted in an overall pregnancy rate (Pearl Index) of 0.20 per 100 woman-years. This combination showed effective cycle control, comparable to other low-dose oral contraceptives (7-10). T h e usual increase in the incidence of breakthrough bleeding and spotting was limited to the first cycles of use. Both the duration and the amount of withdrawal bleeding Table V. Incidence of newly emerging subjective side effects compared with pre-treatment values (% of women) Cycle

N

Nausea

Headache

Total 0 1 3 6

1,684 1,681 1,531 1,307

2.2 4.4 2.9 1.8

7.4 9.3 6.9 5.0

9.9 7.4 5.1 5.3

1.5 5.3 2.7 1.9

6.2 9.3 6.1 4.6

10.4 4.6 3.0 3.3

Breast tension

Pill-starters Table IV. Incidence of irregular bleeding (breakthrough hleeding (BTB) and spotting (YO of women) Cycle 0 1

3 6

BTB

Spotting

Total

1.7 8.2 8.8 5.7

4.5 18.2 9.7 6.7

6.2 26.4 18.5 12.4

0 1

3 6

923 921 828 703

Pill-switchers (from other combined 0 676 3.1 1 676 3.1 3 634 3.4 6 549 1.8

OCs) 9.5 9.6 8.1 5.6

Actu Ohstet Gynecol S a n d

9.9 6.2 5.5 6.3 70 (1991)

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P. Lammers and M . op tea Berg

Table VI. Mean variation in blood pressure

3 6 12

I , 120 902 748

+ 0.4 + 0.8 + 1.0

-0.1 -0.1 + 0.3

decreased with this new preparation, both in the pill-starters as in the pill-switchers. The incidence of subjective side effects was low and comparable t o that seen in women taking placebo contraceptive medication (1 1-12). The further reduction in the estrogen dose per tablet led t o a decrease in the incidence of estrogen-mediated side effects, such as nausea, headache, and breast tension. Moreover, there was no overall effect on blood pressure. The small average increase in body weight (0.3 kg over 12 cycles) is comparable t o body weight demographics in non-OC using women. This increase occurs mainly in adolescent women who still show a tendency to grow. Metabolic studies have shown that this combination has no adverse effects on carbohydrate or lipid metabolism: most of these studies showed an increase in HDL-cholesterol (13-17), an increase of which can be regarded as favourable, since HDL-cholesterol has been recognized as a negative risk factor for ischemic heart disease. Plasma levels of fibrinopeptide A , the first release product in the transformation of fibrinogen into fibrin, were shown to increase during use of this combination, but to a lesser degree then during use of 30 pg EE-containing combined OCs (15,17). The combination of 20 pg E E plus 150 pg desogestrel has thus proved to be an effective, safe and well-accepted ultra-low-dose oral contraceptive.

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Acta Ohstet

Gynecol Scand 70 (IYYI)

oral contraceptives and blood coagulation. Contraception 1979; 20: 257-61. 5. Fotherby K. Effect of oral contraceptives on serum lipids and cardiovascular disease. Br J Family Planning 1985; 11: 8691. 6. Vessey MP. Female hormones and vascular disease. Br J Family Planning 1980; Suppl 6: 1-12. 7. Cullberg G, et at. Two oral contraceptives; efficacy, serum proteins and lipid metabolism. Contraception 1982; 26: 22943. 8. Mall-Haefeli M. Klinische und biochemische Resultatc bei der Behandlung mit Marvelon. Geburtsh Frauenheilkd 1982; 42: 215-22. 9. Bye PGT. Analysis of a multicentre trial of a new low-dose oral contraceptive in Great Britain. Acta Obstet Gynecol Scand 1976; Suppl 54: 61-6. 10. Upton V. Clinical experience with the triphasic oral contraceptive. In: Elstein M, ed. Update on triphasic oral contraception, Amsterdam: Excerpta Medica, 1983: 54-74. 11. Aznar-Ramos R, et al. Incidence of side effects with contraceptive placebo. Am J Obstet Gynecol 1969; 105: 1144-9. 12. Goldzieher JW, et al. A placebo-controlled doubleblind crossover investigation of the side effects attributed to oral contraception, Fertil Steril 1971; 22: 609-23. 13. Tuimala R.Effects of the oral contraceptive combination 0.150 rng desogestrel + 0.020 mg ethinylestradiol on serum lipids, SHBG, glycosylated proteins and plasma antithrombin 111 activity in healthy women. Acta Obstet Gynecol Scand 1987; Suppl 144: 37-9. 14. Falsetti L. A new low-dose estrogen oral contraceptive combination: effects on endocrine parameters and lipid status. Contraception 1987; 36: 489-97. 15. Fioretti P. Clinical and metabolic study of a new pill containing 20 pg ethinylestradiol plus 0.150 mg desogestrel. Contraception 1987; 35: 22943. 16. Kloosterboer HJ. Effects of the oral contraceptive combination 0.150 mg desogestrel + 0.020 mg ethinylestradiol on serum lipids, including the HDL subfractions. Acta Obstet Gynecol Scand 1987; Suppl 144: 33-6. 17. Melis GB. Fibrinopeptide A (FPA) levels during oral contraceptive treatment. Contraception 1984; 30: 575-83. Address for correspondence: Paul Lammers, M.D. Medical Services & Product Surveillance Department Organon International BV P.O. Box 20 5340 BH Oss The Netherlands