CONTRACEPTION
OPEN PROSPECTIVE MULTICENTER TRIAL WITH A NEW MONOPHASIC CONTRACEPTIVE CONBINATION CONTAINING GESTODENE
M. Renier, M.D. and Ph. Buytaert, University Hospital Antwerp, Belgium
Ph.D.
Abstract In a large and open prospective multicenter trial of contraceptive efficacy, 12,250 cycles from 2,378 women, clinical tolerance and acceptability of a new monophasic gestodene combination containing 75 contraceptive mcg (delta-5-levonorgestrel) and 30 mcg ethinyl oestradiol were The objective was to assess efficacy, safety, side studied. effects and cycle control of this oral contraceptive on healthy women using no other additional birth control methods. Two women became pregnant (0.016%) during the trial: There was no effect on systolic both were patient failures. An average weight increase of 0.3 or diastolic pressures. Cycle control was excellent with 95% of the kg was noted. and 98% free of breakthrough cycles free of spotting serious six cycles. No complications after bleeding occurred. There was an overall incidence of 14% reported side effects (after six cycles), indicating that the hormonal combination is well tolerated. It should be noted that 41.4% of the patients had some complaint before starting the complaints, a highly significant For all treatment. improvement was seen during the treatment.
Reprint
requests:
Dr. M. Renier, University Hospital Antwerp, Wilrijkstraat 10, B2650 Edegem, Belgium
Submitted for publication March 13, 1991 Accepted for publication April 4, 1991
MAY 1991 VOL. 43 NO. 5
413
CONTRACEPTION Introduotioa
The aim of using new synthetic progestogens derived from levonorgestrel (13-ethyl series) in oral hormonal contraceptives is to find a combination that has more beneficial effects or absence of any adverse effects on metabolism along with effective contraceptive efficacy, good tolerance and cycle control. Various metabolic side effects of the progestogens are mainly based on their affinity and action to androgenic, glucocorticoid and mineralocorticoid receptors in various target organs (l), including the liver (2). Since gestodene, exerting its progestogenic potency in its original form (3), is approximately three times as biologically active as levonorgestrel, this allows for reduction of the total steroid dose (4). Numerous data suggest that metabolic changes induced by this new low-dose contraceptive preparation are statistically and clinically insignificant. Rare cardiovascular events reported in association with the use of OC pills are of thromboembolic or hypertensive rather than arteriosclerotic origin (5). Therefore, the pronounced potency to counteract any adverse EE-induced effects on coagulation and fibrinolytic system is probably more important. This theoretical protection of the dynamic balance between coagulation and fibrinolysis requires The new hormonal combination exerts further data (6-9). small and probably favorable effects on lipids and lipoproteins relating to the risks of arterial disease (lo12). This positive influence on lipid metabolism is likely to be due to its very low androgenicity. Furthermore, intake of this combination of hormonal compounds is free from adverse effects on glucose metabolism in numerous presentations (13,14). It may be suggested that this new formulation has high efficacy and clinical acceptability primarily due to the total absence of any serious metabolic side effect. Materials and Methods Included in the study were healthy women, aged 16 to 35 years, who took the gestodene combination as a first contraceptive or those who had not used a contraceptive for at least 6 months. Women with known or suspected pregnancy, lactating women, postpartum women whose menses had not returned, women with chronic diseases, vascular problems, with untreated cervical dysplasia, using steroids or other The design of the study was medications, were excluded. carried out by that of a multicenter open trial gynaecologists. Originally, 3,769 patients were included in the trial: 433 patients dropped out without giving a reason, leaving 3,336 patients.
414
MAY 1991 VOL. 43 NO. 5
CONTRACEPTION evaluation, after exclusion for statistical The The protocol violations, was carried out on 2,378 women. women were evaluated after three and six cycles, taking 21 tablets per cycle with the standard seven-day pill-free interval. For this study, 12,250 cycles were statistically evaluated using patient filled-out calendars (daily diary cards) and doctor filled-out case report forms. Descriptive statistics were applied on all variables recorded at the for three visits, using the double data entry technique entering data in the computer. Evaluation of efficacy was primarily based on the while main cycle characteristics number of pregnancies (onset, duration, quantity) were tested using the McNemar variable tests (evolution of the discrete "quantity of bleeding" between two visits) or with repeated measures analysis of variance for the continuous variables (onset, duration). Evaluation of safety was performed in the same using McNemar tests on the number of side effects analysis of variance for weight and blood pressures. Special attention was interruption of the trial. 5% level of significance.
way and
given to side effects causing All tests were two-sided, at a
At onset of the study, 2,378 patients averaged 24.7 (+_ 5.3) years of age, having experienced menarche at 13.0 (2 1.3) years, with a mean duration of menstruation of 5.2 (+ 1.8) days. Moderate blood loss during menstruation was reported by 71.7% of the women, 46.5% had never used contraception while 42.3% had a history of hormonal contraceptives and 9.4% used non-hormonal contraceptives. Patients weighed an average of 58.6 (+ 8.3) kg and had mean blood pressure of 119.7 (+ 10.0)/72.2 (k7.8) mmHg. Results Acceotabilitv In total, 440 patients (18.5%) discontinued the treatment. In Table I, the cumulative reasons for discontinuation are presented. Two-hundred-ninety-six patients (12.4%) discontinued for reasons that might be related to the study medication (pregnancy, irregular bleedings, side effects, or a combination of these). Among patients discontinuing because of side effects (other than cycle control), headache was the most common (N=49), weight gain (N=23), (N=52), along with mastodynia nausea (N=20) and nervousness and acne (both N=13).
MAY 1991 VOL. 43 NO. 5
415
Table I.
Reasons
for Discontinuation
Reason for Discontinuation Visit 2 + Visit 3 Pregnancy Social reasons Desire to have children Side effects Irregular bleedings Hypermenorrhea Hypertension Thrombose (deep) Thrombose (superficial) Others
Contraceutive
Number of Patients v3 Total
0
17 42 142 83 9 2 1 1 45 15 39 9 38 13 9
Nausea Headache Nervousness Mastodynia Weight gain Acne (*) Percentage (N=2378).
v2
of the patients
included
2 10
2 21 71 198 109 15 3 1 3 55
5 13 4 11 10 4
20 52 13 49 23 13
2 4 29 56 26 6
(0.8%)
in the analysis
reliabilitv
Two pregnancies occurred in a total of 2,378 women (0.084%) during the observation period of 12,250 cycles (0.016% per cycle or 0.21% per year). For one of these patients, it was mentioned that she became pregnant because of gastrointestinal problems that caused a malabsorption of the tablets. The other patient forgot to take two tablets. the pill-effectiveness equals zero and the useThus, effectiveness (Pearl Index) equals 0.21. This efficacy was achieved even though, in many cases, one or more tablets had been forgotten: 329 patients mentioned having forgotten to take tablets on visit 2 and 179 patients on visit 3. out of the 2,378 evaluated patients, 339 (14.3%) mentioned that they forgot to take their tablet at least once during the trial. Menstrual
cvcle control
Variables tested concerning menstrual bleeding were day duration, of onset of menses, quantity and absence of bleeding. Descriptive statistics of the variables on the two follow-up visits are shown in Table II.
416
MAY 1991 VOL. 43 NO. 5
CONTRACEPTION
Menstrual
Table II.
Bleeding Variables* Visit 1
Onset of bleeding (day) Duration
(days)
Quantity Little Moderate Heavy
(N)
Amenorrhea
(N)
X
Visit 2
Visit 3
24.6(+1.5) (N=1,957)
24.7(+1.4) (N=1,534)
5.16(+1.7) (N=2,320)
4.1(%1.4) (N=1,975)
4.0(?1.3) (N=1,536)
288(12.3%) 1698(72.7%) 351(15.0%) (N=2,310)
717(34.9%) 1242(61.5%) 73( 3.6%) (N=2,024)
553(35.1% 978(62 .l% 42( 2.7% (N=1,572
6( 0.3%)
8( 0.5%
X
*Visit 1 at intake, visit 2 and 3 after 3 and 6 months, respectively.
Statistical evaluation of the evolution of duration of the bleeding was carried out by means of the t-test for significant decrease was measurements: a highly paired observed (p
OPEN PROSPECTIVE MULTICENTER TRIAL WITH A NEW MONOPHASIC CONTRACEPTIVE CONBINATION CONTAINING GESTODENE
M. Renier, M.D. and Ph. Buytaert, University Hospital Antwerp, Belgium
Ph.D.
Abstract In a large and open prospective multicenter trial of contraceptive efficacy, 12,250 cycles from 2,378 women, clinical tolerance and acceptability of a new monophasic gestodene combination containing 75 contraceptive mcg (delta-5-levonorgestrel) and 30 mcg ethinyl oestradiol were The objective was to assess efficacy, safety, side studied. effects and cycle control of this oral contraceptive on healthy women using no other additional birth control methods. Two women became pregnant (0.016%) during the trial: There was no effect on systolic both were patient failures. An average weight increase of 0.3 or diastolic pressures. Cycle control was excellent with 95% of the kg was noted. and 98% free of breakthrough cycles free of spotting serious six cycles. No complications after bleeding occurred. There was an overall incidence of 14% reported side effects (after six cycles), indicating that the hormonal combination is well tolerated. It should be noted that 41.4% of the patients had some complaint before starting the complaints, a highly significant For all treatment. improvement was seen during the treatment.
Reprint
requests:
Dr. M. Renier, University Hospital Antwerp, Wilrijkstraat 10, B2650 Edegem, Belgium
Submitted for publication March 13, 1991 Accepted for publication April 4, 1991
MAY 1991 VOL. 43 NO. 5
413
CONTRACEPTION Introduotioa
The aim of using new synthetic progestogens derived from levonorgestrel (13-ethyl series) in oral hormonal contraceptives is to find a combination that has more beneficial effects or absence of any adverse effects on metabolism along with effective contraceptive efficacy, good tolerance and cycle control. Various metabolic side effects of the progestogens are mainly based on their affinity and action to androgenic, glucocorticoid and mineralocorticoid receptors in various target organs (l), including the liver (2). Since gestodene, exerting its progestogenic potency in its original form (3), is approximately three times as biologically active as levonorgestrel, this allows for reduction of the total steroid dose (4). Numerous data suggest that metabolic changes induced by this new low-dose contraceptive preparation are statistically and clinically insignificant. Rare cardiovascular events reported in association with the use of OC pills are of thromboembolic or hypertensive rather than arteriosclerotic origin (5). Therefore, the pronounced potency to counteract any adverse EE-induced effects on coagulation and fibrinolytic system is probably more important. This theoretical protection of the dynamic balance between coagulation and fibrinolysis requires The new hormonal combination exerts further data (6-9). small and probably favorable effects on lipids and lipoproteins relating to the risks of arterial disease (lo12). This positive influence on lipid metabolism is likely to be due to its very low androgenicity. Furthermore, intake of this combination of hormonal compounds is free from adverse effects on glucose metabolism in numerous presentations (13,14). It may be suggested that this new formulation has high efficacy and clinical acceptability primarily due to the total absence of any serious metabolic side effect. Materials and Methods Included in the study were healthy women, aged 16 to 35 years, who took the gestodene combination as a first contraceptive or those who had not used a contraceptive for at least 6 months. Women with known or suspected pregnancy, lactating women, postpartum women whose menses had not returned, women with chronic diseases, vascular problems, with untreated cervical dysplasia, using steroids or other The design of the study was medications, were excluded. carried out by that of a multicenter open trial gynaecologists. Originally, 3,769 patients were included in the trial: 433 patients dropped out without giving a reason, leaving 3,336 patients.
414
MAY 1991 VOL. 43 NO. 5
CONTRACEPTION evaluation, after exclusion for statistical The The protocol violations, was carried out on 2,378 women. women were evaluated after three and six cycles, taking 21 tablets per cycle with the standard seven-day pill-free interval. For this study, 12,250 cycles were statistically evaluated using patient filled-out calendars (daily diary cards) and doctor filled-out case report forms. Descriptive statistics were applied on all variables recorded at the for three visits, using the double data entry technique entering data in the computer. Evaluation of efficacy was primarily based on the while main cycle characteristics number of pregnancies (onset, duration, quantity) were tested using the McNemar variable tests (evolution of the discrete "quantity of bleeding" between two visits) or with repeated measures analysis of variance for the continuous variables (onset, duration). Evaluation of safety was performed in the same using McNemar tests on the number of side effects analysis of variance for weight and blood pressures. Special attention was interruption of the trial. 5% level of significance.
way and
given to side effects causing All tests were two-sided, at a
At onset of the study, 2,378 patients averaged 24.7 (+_ 5.3) years of age, having experienced menarche at 13.0 (2 1.3) years, with a mean duration of menstruation of 5.2 (+ 1.8) days. Moderate blood loss during menstruation was reported by 71.7% of the women, 46.5% had never used contraception while 42.3% had a history of hormonal contraceptives and 9.4% used non-hormonal contraceptives. Patients weighed an average of 58.6 (+ 8.3) kg and had mean blood pressure of 119.7 (+ 10.0)/72.2 (k7.8) mmHg. Results Acceotabilitv In total, 440 patients (18.5%) discontinued the treatment. In Table I, the cumulative reasons for discontinuation are presented. Two-hundred-ninety-six patients (12.4%) discontinued for reasons that might be related to the study medication (pregnancy, irregular bleedings, side effects, or a combination of these). Among patients discontinuing because of side effects (other than cycle control), headache was the most common (N=49), weight gain (N=23), (N=52), along with mastodynia nausea (N=20) and nervousness and acne (both N=13).
MAY 1991 VOL. 43 NO. 5
415
Table I.
Reasons
for Discontinuation
Reason for Discontinuation Visit 2 + Visit 3 Pregnancy Social reasons Desire to have children Side effects Irregular bleedings Hypermenorrhea Hypertension Thrombose (deep) Thrombose (superficial) Others
Contraceutive
Number of Patients v3 Total
0
17 42 142 83 9 2 1 1 45 15 39 9 38 13 9
Nausea Headache Nervousness Mastodynia Weight gain Acne (*) Percentage (N=2378).
v2
of the patients
included
2 10
2 21 71 198 109 15 3 1 3 55
5 13 4 11 10 4
20 52 13 49 23 13
2 4 29 56 26 6
(0.8%)
in the analysis
reliabilitv
Two pregnancies occurred in a total of 2,378 women (0.084%) during the observation period of 12,250 cycles (0.016% per cycle or 0.21% per year). For one of these patients, it was mentioned that she became pregnant because of gastrointestinal problems that caused a malabsorption of the tablets. The other patient forgot to take two tablets. the pill-effectiveness equals zero and the useThus, effectiveness (Pearl Index) equals 0.21. This efficacy was achieved even though, in many cases, one or more tablets had been forgotten: 329 patients mentioned having forgotten to take tablets on visit 2 and 179 patients on visit 3. out of the 2,378 evaluated patients, 339 (14.3%) mentioned that they forgot to take their tablet at least once during the trial. Menstrual
cvcle control
Variables tested concerning menstrual bleeding were day duration, of onset of menses, quantity and absence of bleeding. Descriptive statistics of the variables on the two follow-up visits are shown in Table II.
416
MAY 1991 VOL. 43 NO. 5
CONTRACEPTION
Menstrual
Table II.
Bleeding Variables* Visit 1
Onset of bleeding (day) Duration
(days)
Quantity Little Moderate Heavy
(N)
Amenorrhea
(N)
X
Visit 2
Visit 3
24.6(+1.5) (N=1,957)
24.7(+1.4) (N=1,534)
5.16(+1.7) (N=2,320)
4.1(%1.4) (N=1,975)
4.0(?1.3) (N=1,536)
288(12.3%) 1698(72.7%) 351(15.0%) (N=2,310)
717(34.9%) 1242(61.5%) 73( 3.6%) (N=2,024)
553(35.1% 978(62 .l% 42( 2.7% (N=1,572
6( 0.3%)
8( 0.5%
X
*Visit 1 at intake, visit 2 and 3 after 3 and 6 months, respectively.
Statistical evaluation of the evolution of duration of the bleeding was carried out by means of the t-test for significant decrease was measurements: a highly paired observed (p
