P.E. Hall

A multicentred phase III comparative clinical trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100mg or 150mg: 1. Contraceptive efficacy and side effects

Two dosages of depot-medroxyprogesterone acetate (DMPA), 100 mg and 150 mg given every 90 days, were compared in two groups of women with regard to effectiveness, reported complaints and reasons for discontinuation. A total of 1216 women were recruited into a seven-centre, multinational, randomized clinical trial. Follow-up was for a period of one year and resulted in a total of 5507 woman-months of experience of 100 mg DMPA and 5429 woman-months of experience of the 150 mg dose. The study showed little difference in efficacy and side effects between the two treatment groups. Two pregnancies occurred in women receiving 100 mg DMPA giving a Pearl Index of 0.44 per 100 woman-years. None occurred in the 150 mg group. There was no difference in the overall continuation rates between the two groups at one year, being 59.3% in the 100 mg group and 58.8% in the 150 mg group. Except for discontinuation of method use for amenorrhea, the rates of all medical and non-medical reasons given for discontinuation were comparable between the two treatment groups. Womens perception of lack of bleeding was reported as amenorrhea and resulted in discontinuation rates at 12 months for amenorrhea of 7.2% for women receiving 100 mg of DMPA and 12.5% for those receiving the 150 mg dose. Three centres, Alexandria, Karachi and Szeged, made the major contributions to this difference.

Multinational comparative clinical trial of long-acting injectable contraceptives: Norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. Final report: Who special programme of research, development and research training in human reproduction*

Final results are presented from a two-year WHO multinational comparative trial of three regimens: depot-medroxyprogesterone acetate (DMPA) given at 90-day intervals, norethisterone enanthate (NET-EN) given at 60-day intervals for the entire study period (NET-EN (60-day)), and NET-EN given at 60-day intervals for six months and thereafter at 84-day intervals (NET-EN (84-day)). 1587 DMPA subjects were observed for 20,550 woman-months, 789 NET-EN (60-day) subjects were observed for 10,361 woman-months, and 796 NET-EN (84-day) subjects were observed for 10,331 woman-months. This clinical trial represents the largest clinical trial undertaken on injectable contraceptives. After two years, the pregnancy rate with NET-EN (84-day) was 1.4 (+/- 0.6 S.E.) per 100 women, as compared with the two-year rates of 0.4 (+/- 0.3 S.E.) per 100 women observed with DMPA and 0.4 (+/- 0.2 S.E.) with NET-EN (60-day). Both discontinuation rates for amenorrhea and the prevalence of amenorrhea lasting more than 90 days were significantly higher with DMPA than with either NET-EN regimen. Terminations for bleeding problems were similar with the three treatments, despite a better cyclic pattern for the first six months with the NET-EN regimens. The three treatments were comparable with respect to discontinuation rates for other medical or personal reasons, and for all reasons combined. For family planning programs, NET-EN (60-day) has the advantage of low pregnancy rates compared to NET-EN (84-day), and a schedule of administration that does not change. Both NET-EN regimens produce less amenorrhea than DMPA. However, the NET-EN (60-day) regimen has the logistic and economic disadvantage of requiring more frequent injections. All three injectable regimens compare favourably with oral contraceptives in terms of pregnancy and total continuation rates observed in clinical trial settings.

A randomized, double-blind study of two combined and two progestogen-only oral contraceptives.

A randomized double-blind study of two combined oral contraceptives and two progestogen-only oral contraceptives was conducted using the same protocol at WHO Collaborating Centres for Clinical Research in Human Reproduction in Bombay and Ljubljana of the 518 women admitted to the trial, 123 received mestranol 50 micrograms + norethisterone 1mg (MES 50 + NET 1); 137 received ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (EE 30 + LNG 150); 130 received norethisterone 350 micrograms/NET 350); and 128 received levonorgestrel 30 micrograms (LNG 30). At one year, between 52.6 and 61.0 percent of those recruited had discontinued oral contraceptive use for all reasons, and by two years, between 70.5 and 76.5 percent had discontinued the treatment. These rates did not differ between the four treatment groups. However, discontinuation rates for all medical reasons at one and two years, and at two years pregnancy rates and discontinuation rates for bleeding disturbances, were significantly lower in the EE/LNG preparation. The groups receiving the MES/NET, LNG and NET had similar pregnancy rates, discontinuation rates for all medical reasons and all bleeding disturbances. There were two ectopic pregnancies among the 22 pregnancies in the progestogen-only groups. Discontinuation because of headache, dizziness and other central nervous system symptoms were significantly more common in those receiving MES/NET compared to EE/LNG. In contrast, discontinuation for gastro-intestinal disturbances were significantly higher in the EE/LNG combined preparation. Bleeding disturbances in the first few cycles tended to be higher in NET than in the LNG group. The data suggest that greater consideration be given to the benefits and risks of including progestogen-only oral contraceptives in the family planning programmes of some countries.

A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection: II. The comparison of bleeding patterns

A multicentred Phase III clinical trial was conducted in 12 countries to compare HRP112 (depot-medroxyprogesterone acetate, 25 mg and estradiol cypionate, 5 mg) and HRP102 (norethisterone enantate, 50 mg and estradiol valerate, 5 mg) given every 28 days. Contraceptive efficacy and side-effects of both regimens were reported previously. Their effect on vaginal bleeding patterns is the object of this paper. A total of 2320 women were randomly assigned to each drug and 2000 of them provided a menstrual diary. The comparison of the bleeding patterns is made using a 90-day reference period approach and following the guidelines published by WHO. The analysis failed to identify any major difference in the vaginal bleeding patterns induced by both contraceptive preparations. For both drugs, the first bleeding episode following the first injection occurs early. For 70% of users, this is followed by a regular vaginal bleeding pattern similar to an untreated pattern. Others experience irregular bleeding and a few have either infrequent or frequent bleeding. The extremes of amenorrhea and prolonged bleeding are rare. There are no major trends in vaginal bleeding patterns with prolonged use of either preparation. Women with the worst vaginal bleeding patterns discontinue early in the clinical trial and the last three months of experience have the most influence in their decision to stop using the contraceptive method. The analysis suggests how the life-table analysis of discontinuation reasons underestimates the true incidence of vaginal bleeding irregularities in a clinical trial.

A multicentred pharmacokinetic. pharmacodynamic study of once-a-month injectable contraceptives I. Different doses of HRP112 and of depoprovera

Abstract A multicentred study was undertaken at three institutions in Hungary, Mexico and Thailand in women of reproductive age to evaluate the effects of full and half doses of HRP112 (depot-medroxyprogesterone acetate (DMPA) plus estradiol cypionate) and DMPA alone on ovarian function, bleeding patterns and HDL-cholesterol levels. Full dose HRP112 contained 25mg DMPA plus 5mg, of estradiol cypionate and the half dose, 12.5mg DMPA plus 2.5mg of estradiol cypionate. The full and half dose DMPA were 25 and 12.5mg respectively. In all, 88 women were recruited in the study and randomized within each centre, to the four treatment groups. Subjects were studied for a control cycle, three one-month injection intervals and followed-up for a further two months. Serum concentrations of estradiol, progesterone and medroxyprogesterone acetate were determined three times a week during the third injection interval and during the two months of follow-up. While the results from all centres indicated that the four preparations were all effective in inhibiting ovulation for at least one month, there were marked between centre differences in pharmacokinetic profiles. More regular bleeding patterns were observed in women who received the estrogen-progestogen combination preparations than in those who received DMPA alone.

A randomized, double-blind study of six combined oral contraceptives

A randomized controlled clinical trial comparing six combined oral contraceptives with 50 micrograms or less of ethinyl estradiol was undertaken in 10 WHO Collaborating Centres for Clinical Research in Human Reproduction. A total of 2430 women entered the trial and were observed for 28,077 woman-cycles. All low-dose combined oral contraceptives demonstrated equivalent efficiency with one-year pregnancy rates of one to six percent. However, discontinuation rates for medical reasons differed significantly between the treatment groups, with the preparation containing 20 micrograms ethinyl estradiol and that containing 400 micrograms norethisterone acetate being associated with higher discontinuation rates due to bleeding disturbances. Even among the preparations which did not differ in discontinuation rates, the reasons for discontinuation did differ. Women receiving norethisterone preparations tended to discontinue because of bleeding disturbances while those receiving the levonorgestrel-containing preparations tended to discontinue because of complaints of nausea and vomiting.

A multicentred phase III comparative clinical trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100mg or 150 mg: II. The comparison of bleeding patterns

Abstract A multicentered phase III clinical trial was conducted in seven countries to compare two dosages of depot-medroxy progesterone acetate (DHPA), 100mg and 150mg, given every 90 days. Contraceptive efficacy and side-effects of both regimens were reported previously. Their effect on vaginal bleeding patterns is the object of this paper. A total of 1216 women were randomly assigned to a dose group and 1156 of them provided a menstrual diary. The comparison of the bleeding patterns is made using a 90-day reference period approach and following the guidelines published by WHO. In addition, the longest bleeding/spotting episode and the longest bleeding/spotting-free interval are calculated over the entire diary lengtn. The only dirterence found between the two dose groups is a higher incidence of amenorrhea with the 150mg regimen. Overall, there is a high degree of consistency between the reasons given by individual women for discontinuing the contraceptive method and their vaginal bleeding pattern during the 90 days preceding discontinuations. However the data revealed large between-centre differences, both in the incidence of specific patterns, and in the identification by women of bleeding problems as reasons for discontinuation. This last point suggests that the life-table analysis underestimates the true incidence of menstrual irregularities. Comments on the reference period analysis method are made.

A multicentred phase III comparative clinical trial of mesigyna, cyclofem and injectable No.1 given monthly by intramuscular injection to Chinese women. I: Contraceptive efficacy and side effects

A phase III clinical study was carried out among 5680 fertile Chinese women to evaluate efficacy and side effects of three monthly injectable contraceptives: Mesigyna, Cyclofem and Chinese Injectable No. 1. When used in a once-a-month treatment schedule (part 1 of study), the effectiveness of Chinese Injectable No. 1 was unacceptably low; 36 pregnancies occurred during the first 1743 women-months of use, 16 before the second injection. The study was restarted with a revised injection schedule for Injectable No. 1: two injections separated by 9 +/- 1 days during the first month and subsequent injections given 10-12 days after the onset of bleeding, or if no bleeding occurred, 28 days after previous injection. In part 2 of the study, 988, 990 and 992 subjects were provided Mesigyna, Cyclofem and Injectable No. 1, respectively. Life-table pregnancy rates at one year were 0.41%, 0% and 0.77% (p < 0.05), respectively; the overall discontinuation rates at one year were 13.9%, 19.1% and 20.4% (p < 0.001). Discontinuation rates for bleeding problems were significantly different between the groups: discontinuation rates for amenorrhea were 0.58%, 3.71% and 0.68% (p < 0.001) for Mesigyna, Cyclofem and Injectable No. 1; for other bleeding problems, the rates were 4.88%, 8.38% and 12.64% (p < 0.001). There were no significant differences between the groups regarding discontinuation for other medical or non-medical reasons. Mean weight changes after one year of use were small: 0.73, 0.86 and 0.17 kg for the three groups, respectively. Both Mesigyna and Cyclofem were very effective for contraception, but Mesigyna appeared to be tolerated slightly better with regard to cycle control; the modified dose regimen for Injectable No. 1 also gave a low pregnancy rate but was associated with higher rates of discontinuation.

Long-acting hormonal contraceptives for women

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organizations (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

Introductory study of the once-a-month injectable contraceptive Cyclofem in Brazil Chile Colombia and Peru.

An introductory trial with the injectable contraceptive Cyclofem was carried out in Brazil, Chile, Colombia, and Peru, with participation by 3,183 women. Women were followed-up for up to 2 years of use and the data were evaluated by life table analysis. A total of 29,676 women-months were accumulated for up to 2 years. No pregnancies were observed in the 2 years. The discontinuation rates for amenorrhea in the first year ranged from 3.4 in Brazil to 8.1 in Colombia, and for menstrual disturbances from 5.1 in Chile to 9.2 in Brazil. The discontinuation rates for other medical reasons ranged from 7.8 in Brazil to 26.3 in Colombia, and for personal reasons from 17.2 in Chile to 23.5 in Brazil. Continuation rates ranged from 42.3 in Colombia to 52 in Chile. In the second year of observation the rates of discontinuation were lower than those observed in the first year, with the exception of personal reasons in Brazil, which were the same as those observed in the first year. Continuation rates ranged from 19.4 in Brazil to 36.8 in Chile. The comparison of reasons for discontinuation in selected clinics showed that the rate for amenorrhea in one clinic in Chile was more than three times that in others and in Peru was seven times more in one clinic than in another. Regarding menstrual disturbances, in Peru one clinic presented a rate three times higher than the others. The main reasons for discontinuation due to other medical reasons were headache and weight gain. In conclusion, Cyclofem presented a high contraceptive efficacy and an acceptable rate of continuation and discontinuation for up to 2 years in the four countries.