A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection

CONTRACEPTION

A~TIC~~KIII~~TIVESTUDYOFTVOHOBWONAI. CONTRACEPTIVE PREPARATIoRS GIVEN ONCE-A-IfONTHBY INTRAMUSCUIAR INJECTION II. THE COMPARISON OF BLEEDING PATTERNS WORLD HEALTH ORGANIZATION Special Programme of Research, Development and Research Training in Human Reproduction Task Force on Long-Acting Systemic Agents for Fertility Regulation

S. Said, W. Sadek and A. Kholeif Department of Obstetrics and Gynaecology, Shatby Hospital, University of Alexandria, Alexandria, Egypt Suporn Koetsawang, Orawan Kiriwat and Surat Piboonmanee Family Planning Research Unit, Siriraj Hospital, University, Bangkok, Thailand

Maternity

Mahidol

R. Rivera, G. Alvarado, M.A. Juarez and S. Aquilar Instituto de Investigaciones Cientificas, Universidad Juarez de1 Estado de Durango, Durango, Mexico R. Santiso, C.F. Contreras, L.F. Galichl and M. Guirola Asociacion Pro-Bienestar de la Familia de Guatemala (APROFAM), Guatemala City, Guatemala M.G. Alzugaray, M.L. Hernandez and J.R. Gallarco Institute of Endocrinology and Metabolic Diseases, Hospital 'Cmdte Fajardo', and Hospital 'Gonzalez Core', Havana, Cuba B. Affandi, S.S.I. Santoso and R.S. Samil Klinik Raden Saleh, Department of Obstetrics and Gynaecology, University of Indonesia, -Jakarta Pusat, Indonesia A. Kazi National Research Institute of Fertility Control, Population Welfare Division, Karachi, Pakistan E.S. Kononova and V.I. Alipov Institute of Obstetrics and Gynaecology of the Academy of Medical Sciences, Leningrad, USSR R. Apelo, E.S. Bernard0 and I. Benitez Jose Fabella Memorial Hospital, Manila, Philippines T. Canto-de-Cetina, S. Cardenas, L. Polanco and L. Vera Regionales 'Dr Hideyo Noguchi', Centro de Investigaciones ._ . Universidad Autonoma de Yucatan, Merida, Yucatan, Mexico

Submitted for publication November 17, 1988 Accepted for publication August 10, 1989 NOVEMBER 1989 VOL. 40 NO. 5

531

CONTRACEPTION M.C. Cravioto, L. Hernandez, J.L. Fuziwara, J. Garza-Flores and G. Perez-Palacios Department of Reproductive Biology, Instituto National de Nutrition, Salvador Zubiran, Mexico City, Mexico (coordination of Mexican network centres) G. Oropeza, E. Mota and E. Zavaleta Family Planning Clinic, General Hospital of Mexico, Mexico City, Mexico G. Benagiano and C. Bastianelli Instituto de Ia Clinica Ostetrica et Ginecologica, Universita 'La Sapienza', Roma, Italy A. Diaz Infante-Ibarra (deceased), C.J. Castelo, R. Jiminez and N. Perez-Arocha Biologia de la Reproduction, Facultad de Medicina, Universidad Autonoma de San Luis de Potosi, San Luis de Potosi, Mexico J. Lang-Prieto, J.A. Casas-Fernandez, H.M. Perez-Paz (deceased), M. Perez, A.R. Hernandez and C. Bustillo Tur Hospital Maternidade Norte and Hospital Provincial Docente 'Saturnino Lora', Santiago de Cuba, Cuba L. Kovacs and S. Koloszar Department of Obstetrics and Gynaecology, University Medical School of Szeged, Szeged, Hungary S. Basso1 and A.M. Trujillo Department of Reproductive Biology, Hospital Universitario, Universidad Autonoma de Coahuila, Torreon, Coahuila, Mexico R. Guzman-Serani and E. Israel Instituto de Obstetrica y Ginecologia, Escuela de Medicina, Universidad Austral de Chile, Valdivia, Chile C. d'Arcangues, B. Busca, P.E. Hall, D. Machin*, A. Pinol and F. Schlagenhaft, Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, 1211 Geneva 27, Switzerland *Also Medical Statistics and Computing, Southampton, Southampton, United Kingdom

University

of

Reprint requests and address for correspondence: d'Arcangues, Special Programme of Research, Development and C. in Human Reproduction, World Health Research Training Organization, 1211 Geneva 27, Switzerland

NOVEMBER 1989 VOL. 40 NO. 5

CONTRACEPTION ABSTRACT 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 go-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 For 70% of users, following the first injection occurs early. 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. INTRODUCTION Injectable contraceptive preparations have been used in family planning programmes for many years. The most widely used are progestogen-only methods, namely depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN). However both in vaginal bleeding patterns which induce major disruptions greatly affect their acceptability (1,2). Over the years, the World Health Organization's Special Programme of Research, Development and Research Training in Human Reproduction designed and implemented a strategy for the development of new injectable contraceptives with high safety and high efficacy and little menstrual disturbances. This led to the formulation and optimization of two once-a-month preparations, both combinations of an estrogen and a progestogen, namely HRPll2 (depot-medroxyprogesterone acetate, 25 mg and estradiol cypionate 5 mg) and HRP102 (norethisterone enantate, 50 mg and estradiol valerate, 5 mg). Details of their development have been reviewed elsewhere (3).

NOVEMBER 1989 VOL. 40 NO. 5

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Both preparations were tested in a large Phase III comparative clinical trial conducted in 12 countries. The study showed little difference in efficacy and side-effects between the two formulations. The cumulative life-table pregnancy rate at 12 months was 0 per 100 woman-years for HRP112 and 0.18 for HRP102. The continuation rates at one year were 64.5% for the HRPll2 users and 63.2% for the HRPlO2 group. Discontinuation rates for vaginal bleeding irregularities were 6.3% and 7.5% for HRP112 and These results have been published HRPlOP, respectively. previously in a paper (4) hereafter referred to as Paper I. This paper presents a detailed analysis of the menstrual diaries recorded by 2000 (86%) of the women recruited to the trial. The vaginal bleeding patterns induced by both preparations are compared and the discontinuation reasons are investigated in relation to the diaries. MATERIALS AND METHODS Desien of the study The preparations used in this study were HRP102 (norethisterone enantate, 50 mg and estradiol valerate, 5 mg) formulated as a 1 ml oily solution and HRPll2 (medroxyprogesterone acetate, 25 mg and estradiol cypionate, 5 mg), previously known as Cycloprovera, formulated as a 0.5 ml aqueous microcrystalline suspension. Both preparations were given every 30 + 3 days as deep intramuscular injections in the gluteal region. Details of the study design, subject selection and follow-up have been presented in Paper I. A total of 2320 women entered the study in 17 centres distributed in 12 countries worldwide: of these, 2000 provided a menstrual diary with daily record of the occurrence of bleeding, spotting or neither. Bleeding was defined as 'any bloody vaginal discharge that requires the use of such protection as pads or tampons' and spotting as 'any bloody vaginal discharge that is not sufficient to require protection'. If a woman decided to leave the trial in mid-course, she was asked her reason for discontinuation. Her answer was then classified into one of several categories: a vaginal bleeding problem further detailed as 'prolonged bleeding', 'heavy bleeding', 'heavy and prolonged bleeding', 'irregular bleeding', 'other menstrual' or 'amenorrhea‘; 'pregnancy', 'spotting', 'other medical reasons', 'desire for pregnancy', 'no further need for contraception' and 'other personal reasons'. The subjects who remained in the trial for the full twelve injection intervals were listed as having reached the 'end of study', while those who failed to return to the clinic for a scheduled injection were listed as 'lost to follow-up'.

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NOVEMBER 19&9VOL. 40 NO. 5

CONTRACEPTION Statistical procedures The comparison of bleeding patterns obtained from the menstrual diaries is made using the reference period approach first suggested by Rodriguez et al. (5) and following the guidelines published by WHO (6). In summary, the menstrual diary is divided into four reference periods of 90 days starting on the day of first injection and finishing 360 days later at the (approximate) anniversary of the first injection. For each woman the following six summary statistics are calculated from her diary for successive reference periods: number of bleeding/spotting days number of bleeding/spotting episodes mean length of bleeding/spotting episodes mean length of bleeding/spotting-free intervals number of spotting days number of spotting-only episodes Within a reference period, all events are taken as complete even if only one day long or truncated by the go-day limit(s). Subjects with no bleeding nor spotting throughout an entire reference period are included in the calculations of summary statistics. For those diaries which are not completed for 360 days, for example from women who refused injections or were lost to followup* a reduced number of reference periods is consequently available. The minimum length of usable diary in any reference period is taken as 60 days; for these short diaries, the numbers of days and episodes are calculated on a proportionate basis. For example if a woman has two bleeding episodes in 70 days of diary, she is credited with 2 x 90/70 - 2.6 episodes for the reference period. In addition to the reference periods defined from the date of the first injection, the menstrual diary 90 days prior to the day of discontinuation of method use is also summarized for each woman. For each summary statistic, the median and interquartile range (interval between the 25th and the 75th percentiles) are calculated and a modified box-whisker plot is used to illustrate the distribution of the summary statistic by reference period. Each woman is also classified into one of seven 'clinically important‘ groups of bleeding pattern as suggested in the WHO guidelines (6). These patterns are determined in each successive go-day reference period for which the woman has provided a complete diary as follows:

NOVEMBER 1989 VOL. 40 NO. 5

535

Patterns classified as 'clinically unacceptable': no bleeding throughout the reference period; at least one bleeding/spotting prolonged bleeding: episode lasting more than 14 days; more than 5 bleeding/spotting frequent bleeding: episodes; infrequent bleeding: 1 or 2 bleeding/spotting episodes irregular bleeding: 3 to 5 bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 days or more; combinations of the above categories; A pattern classified as 'clinically acceptable': none of the above, that is a pattern with 3 to 5 bleeding/spotting episodes, none longer than 14 days and at least 3 bleeding/spotting-free intervals of 14 days or more. To assess changes in vaginal bleeding patterns with respect to the presence of 'clinically unacceptable' patterns in successive reference periods, the methodology suggested by Machin et. (7) is adopted. This links the experience of each woman in her successive reference periods and enables an assessment of worsening, no change or improving patterns with successive injections. The likelihood of a woman accepting subsequent injections can also be related to her total experience up to that time and her experience in the immediate reference period just completed. RESULTS 1.

Comparison of results

Table I compares the summary statistics for each reference period following the first injection by contraceptive method. The number of diaries available for analysis in successive reference periods is also indicated. The data emphasize differences in bleeding patterns between the first reference period and the following ones. The median numbers of bleeding/spotting days, bleeding/spotting episodes, spotting days and spotting-only episodes are greater than in the following reference periods. The mean length of bleeding/spotting-free intervals is shorter during the first reference period than during the following ones. By contrast there are no clinically important differences between The mean length of reference periods II, III and IV. bleeding/spotting episodes appears approximately constant over all reference periods. There appears to be no substantial differences between the two injection methods with respect to any of the summary statistics.

535

NOVEMBER 1989 VOL. 40 NO. 5

CONTRACEPTION

Table I. Comparison of HRP112 and HRPlO2 using reference period analysis

I1 days 91-180

1

days I-90

Ill days 181-270

InterquaItila Interquartilc Interqlwtill h dedian Range I IvIcdian Range* hdedian Range

IV days 91-W 1ntequartiIe ledian Range

112 102

18.0 18.0

11.0 10.0

16.0 15.0

7.8 7.9

15.0 14.5

9.0 8.0

15.0 14.0

9.0 9.0

Number of B/S episodes

112 102

4.0 4.0

2.0 1.0

3.0 3.0

1.0 1.0

3.0 3.0

1.0 1.0

3.0 3.0

1.0 1.0

Number of spotting days

112 102

7.0 7.0

9.0 8.0

6.0 6.0

7.0 7.0

6.0 6.0

7.0 6.0

5.9 6.0

7.0 6.9

Number of spotting-only episodes

112 102

1.0 1.0

1.0 1.0

0.0 0.0

1.0 1.0

0.0 0.0

1.0 1.0

0.0 0.0

1.0 1.0

Mean length of B/S episode

112 102

4.5 4.2

2.1 2.2

5.0 4.5

2.3 2.0

4.5 4.5

2.1 2.0

4.5 4.5

2.0 2.3

Mean length of B/S free interval

112 102

18.0 17.6

8.3 5.6

19.1 19.0

7.0 7.5

19.5 19.5

7.6 7.5

19.5 20.0

7.8 7.8

Number of diaries for analysis

1lZ 102

l

-

1001 999

1

885 860

802 766

730 713

Interquartile range = interval between 25th and 75th percentiles.

537

Figure 1 shows the modified box-whisker plot of the number of bleeding/spotting days by reference period and injection group. The figure illustrates the extra bleeding/spotting days in the first reference period experienced by the women using both preparations. Thereafter the median number of bleeding/spotting days gradually reduces to approximately 15 over successive reference periods. The women receiving HRPlO2 appear to experience more variability about this median than do the women receiving HRP112. Table II shows the percentage of women in each injection group experiencing clinically important bleeding patterns in each successive reference period. In the HRPlO2 and HRPll2 groups, 37.1% and 43.3% of women had 'clinically unacceptable' bleeding disturbances in the first reference period. Both these figures fell in the second and third reference periods to approximately 29%, rising to 34.6 and 34.1%, respectively, in the final reference period. The most common 'unacceptable' bleeding pattern was 'irregular bleeding', particularly in the first and fourth reference periods. The next most common were 'infrequent' and 'frequent' bleeding which showed trends with time. Thus, as the year progressed, fewer women had five or more bleeding/spotting episodes per reference period and more had only one or two. There appear to be no major or consistent differences between injection types. 2.

Relations between discontinuation

the

bleedine

uatterns

and reason for

Table III shows the summary statistics for the 90 days prior to discontinuation by reason given by the subject for discontinuation. There appears to be some consistency between the bleeding patterns and the discontinuation reasons. Those subjects who discontinued for 'amenorrhea' had the least number of bleeding/spotting days, number of spotting days, the shortest and least frequent bleeding/spotting episodes and the longest bleeding/spotting-free intervals. The subjects who discontinued for 'heavy', 'prolonged' or 'heavy and prolonged' bleeding experienced the greatest number of bleeding/spotting days. Among them, those who discontinued for 'prolonged' bleeding had the shortest mean length of bleeding/spotting-free interval. Moreover there was no evidence that women who gave reasons unrelated to bleeding for discontinuation, experienced great disturbances in vaginal bleeding pattern. In fact the summary statistics for these groups were very similar to those of the subjects who completed the study. There were no marked differences between the two preparations for any of the discontinuation groups. In a separate analysis done for both drugs combined, a comparison was made between the reason for discontinuation given by the women and the "clinically important" bleeding patterns they experienced in the reference period preceding their discontinuation. Overall the patterns matched the discontinuation reasons related to vaginal bleeding with two exceptions: of the

538

NOVEMBER 1989 VOL. 40 NO. 5

1 0

10

+aID---

I

20

J

40

I 50

=

832

I

1001

5th

I 70

50th

75th

FIG. 1

Percentiles

25th

95th

--I 0

-

10

30

I

40

102

Days

HRP

PERIOD

maximum

20

COMPARATIVE TRIAL OF HRP 112 AND HRP 102 MENSTRUAL BLEEDING ANALYSIS NUMBER OF BLEEDING/SPOTTING DAYS PER REFERENCE

I 60

‘”

“’

REFERENCE PERIOD

n=730

*=

”

LEGEND. E minimum

I

112

Days

30

I

HRP

50

I 60

n = 713 ,

” = 766

I 80

I,‘,,0 “slnli

, 70

Table II. Number of women (percentage) experiencing different types of bleeding patterns in each reference period by method use

I

ReferencePtriod

L-_--_

BleedingPatterns Method

T-

11 davs91-180

I days I-90

111 days 181-270

Iv days 271-360

Bleeding

Infrequent

HRPllz HRP102

53 29

(5.3) (2.9)

122 102

(13.8) (11.9)

136 96

(17.0) (12.5)

87 80

(11.9) (11.2)

Frequent Bleeding

HRPlL? HRPlO2

92 134

(9.2) (13.4)

22 34

(2.5) (4.0)

19 14

(2.4) (1.8)

22 17

(3.0) (2.4)

Irmgular Bleeding

HRPllz HRP102

235 167

(23.5) (16.7)

102 98

(11.5) (11.4)

64 85

(8.4) (11.1)

118 117

(16.2) (16.4)

Prolonged Bleeding

HRPll2 HRPlM

3 3

3

(0.7) (0.3)

1 3

(0.1) (0.4)

1 2

K-w (0.3)

Prolonged dr Irregular

HRPllZ HRP102

34 23

(3.4) (2.3)

6 10

(0.7) (1.2)

2 9

(0.2) (0.4)

4 14

(0.5) (2.0)

Prolonged & hfmqwnt

HRPllZ HRPlO2

5 1

(0.5) (0.1)

0 2

(0.0) (0.2)

2 1

(0.2) (0.1)

0 1

(0.0) (0.1)

Prchnged 8 Frequent

HRPll2 HRPlM

8 12

(0.8) (1.2)

3 1

(0.3) (0.1)

0 2

(0.0) (0.3)

0 2

(0.0) (0.3)

No Bleed@

HRPll2 HRPlO2

3 2

(0.3) (0.2)

2 6

(0.2) (0.7)

9 10

(1.1) (1.3)

17 14

(2.3) (2.0)

HRPllZ HRPlO2

433 371

(43.3) (37.1)

220

(W.1) (28.7)

249 247

(34.1) (34.6)

HRP112

568 628

(56.7) (62.8)

569

(70.9)

481 466

(65.9) (65.4)

‘Unacceptable’ patterns(total) ‘Acceptable’ pattern

540

I HRP102I

CO.31 (0.3)

6

2%

(29.7) (29.8)

622 604

(70.3) (70.2)

263

-

233

546 L

(71.3)

-

NOVEMBER 1989 VOL. 40 NO. 5

*&k&n

-

112 102

I12 102

112 102

112 102

I

l

Amcnonhs.

IWY Ilading

R0h%lgCd Bleeding

and folongcd Irrcgldv Ikding Bleeding Spotting

cwy Oh Bleeding Rablcmr &g-Y

h8a Needs

uasuu

NO

Mdic8l

Ihim

OlhCl Otha Rmaul RCrmU

1_atefor Lost to 1njccIilm Follow-up

723 706

17 8

4 IO

I8 14

7.5 (1.4) 4.0 (2.2) 4.1 (4.1) 4.3 (2.0) 5.2 (1.7) 4.6 (2.5) 4.8 (3.0) 4.7 (3.0) 5.3 (2.8) 4.5 (2.3) 6.3 (3.4) 8 1 WY) 4.8 (3.5) 6.6 (5.4) 7.1 (3.2) 3.3 (2.2) 3.2 (7.5) 4.0 (3.1) 4.0 (1.6) 3.3 (1.9) 4.0 (1.5) 3.3 (2.0) 4.0 (1.5) 4.3 (2.7)

4.6 (2.2) 4.7 (2.7)

7.6(14.2) 6.4(10.7)

0.0 (0.8) 0.0 (1.0)

0.0 (1.0) 0.0 (1.0)

19.0(5.8) 28.5 (10.0) I19.2(6.6) 41.8 wl.5)

YXi(l6.0;10.0(18.9) 4.5(14.0) 6.0 (5.4)13.1(19.8) 9.8 (8.2) 7.0 (6.3) 6.0 (6.0) 7.0 (8.8) 7.0 (6.0) 6.0 (9.0) 6.0 (6.3) 35.0(24.0) 16.0(15.8) 8.0 (8.0) 4.0 (8.1) 5.5 (6.0) 6.0 (6.1) 7.0 (7.2) 6.6 (7.7) 7.0 (9.0) 20.9(12.9) 7.ql9.0) 10.5CI4.4)

6.0 (7.0) 4.0 (7.0) 6.0 (7.0) 2.1 (6.4)

8 I5

,

7 12 I

4 7 ,

7 6

49 52 I

25 26 I

16 24 I

43 49 r

4.8 (8.1) 18209.4) 13.8(27.8)12.7(10.7) 8.0 (3.1) 19.2 (9.3) l8.6(lO.2)18.2 (7.3) 18.7 (9.8) 18.8 (9.6) 3.0(13.3) 9.9 (7.3) 9.5(12.7)15.4(I1.9) 8.5 (5.6) 18.8 (6.1) 18.7 (6.4) 18.7 (3.2) I7.5 (5.4) 23.8 (9.2)

0.0 (0.0) 0.0 (1.4) 1.0 (7.3) I.4 (2.0) 0.0 (1.0) 1.0 (1.0) 0.0 (1.8) 0.0 (1.0) 0.0 (1.0) 0.0 (2.0) 0.0 (1.0) 1.0 (1.5) 3.0 (2.0) 1.5 (4.0) 0.0 (1.8) 0.0 (1.0) 0.0 (1.0) 0.0 (1.1) 0.0 (1.0) 0.0 (1.1)

4.0 (3.3; 4.0 (2.0) 4.0 (1.0) 4.0 (5.0) 4.1 (7.5) 4.0 (4.0) 3.0 (1.0) 3.0 (1.0) 3.0 (1.5) 3.0 (1.0) 3.0 0.5) 3.0 (1.5) 3.5 (2.81 4.0 (1.5) 4.0 (3.0) 6.0 (3.0) 5.0 (2.0) 4.5 (3.3) 3.0 (1.0) 3.0 (1.0) 3.0 (1.0) 3.0 (1.0) 4.0 (1.0) 3.0 (2.0)

3.0 (l.Oj 3.0 (I.01

26.0(24.8)17.1(20.0) 17.0 (6.5) 13.0(10.0)14.5 (7.5) lS.O(l2.0) I 6.0(11.4) 14.0 (9.6) 15.0(8.0: 7.0 (9.4) 11.OU6.0 29.5 (7.3; i9.0(8.3) 17.0(13.0) 23.5t23.3) 42.0(38.0)22.0 (5.0) IS.8 (9.5) 14.5(11.5)15.0 (6.5) 14.5 (8.0) I 7.4 (9.3) 14.0 (6.5) 33.5(31.3) 17.0(19.0) IS.0(9.0: 4.2 (8.5) !4.0(12.5,

Fnd of Study

withLheinlerquarlile rangeshominpprcmhcses.

Numberofditiea fc#urllysir

NumbcrafB/Sday

RcfunvrPcriad 9Qdays immediael priamdiscaotinuMelho d uicm __

Table III. Summary statistics of 90&y reference period immediately prior to discontinuation

f

8

CONTRACEPTION

25 women discontinuing for amenorrhea, only two had patterns of 'no bleeding' while 16 fell in the category of 'infrequent' bleeding. Similarly, of the 137 women who discontinued for bleeding-related reasons, 31 or 23% were categorized as having 'acceptable' vaginal bleeding patterns. Among the 434 women who discontinued for a non-bleedingrelated reason, 42.8% had an 'unacceptable‘ pattern. For 14.5%, this was 'infrequent bleeding' and for 18.0% 'irregular bleeding'. 3.

Centre differences

Table IV summarizes the experience in each centre by indicating the percentage of women with an 'acceptable' vaginal bleeding pattern for each reference period, as well as the 12month life-table discontinuation rates for menstrual reasons and all reasons. Centres are listed in order of decreasing discontinuation rates for menstrual reasons. The centre with the highest percentage of women with an 'acceptable' vaginal bleeding pattern is Alexandria, with 89.5% in the third reference period and 97.0% in the fourth reference period. However, the effect of the discontinuations is unknown. It is thought that women with the most disruptive vaginal bleeding patterns tend to discontinue contraceptive use early in the clinical trial so that any improvement in the overall experience of the women may in fact by spurious. In Alexandria the 12-month life-table discontinuation rate for menstrual reasons is 15.9%, one of the highest in this clinical trial. In other centres such as Leningrad, Szeged and Merida, the percentage of women with an 'acceptable' vaginal bleeding pattern increases with time. But these centres also have 12-month lifetable discontinuation rates of 29.1% to 42.0% for all reasons, of which 3.8% to 9.0% are for menstrual reasons. In fact, the table illustrates how discontinuation patterns vary from centre to centre. For example, the percentages of 'acceptable' vaginal bleeding patterns are similar in Manila and Karachi for each reference period. Yet in Manila, the 12-month life-table discontinuation rate for menstrual reasons was 0.9%. compared to 24.8% in Karachi. The best approximation of the real effect of once-a-month injectables with time can be drawn from centres with low discontinuation rates. Jakarta and Valdivia are such centres, with no discontinuation for menstrual reasons and with low discontinuation rates for all reasons, 10.5 and 15.1%, respectively. In both centres there is an improvement in the percentage of women with an 'acceptable' vaginal bleeding pattern from reference period I to reference period II, with an increase of 1.5% and 20.9%, respectively. This is followed by a gradual decline in this percentage over the next six months, from 73.075.7% to 54.6-57.5%.

542

NOVEMBER 1989 VOL. 40 NO. 5

CONTRACEPTION

Table IV. Pcrcentagcof women with an ‘acceptable’vaginal bleeding pattern.rankedby decreasingdiscontinuationrate for mcnsirual reasons, for each rcfcrmcc period and ccntre ‘Amptnbk’

PIlternr (8)

Referena I CalIrE

days 1-w

KUShi

68.7 (lg2)*

Rmle

II days 91-180

36.0

Sm Luis

Alexmdria

Gumanak Cii

Cuba, HIVrm

-end

Cuba. Sauiago

szegcd

Mexico. Tonwm

Icxiw. Mexico City

Mexico. Meric!a

BIllgkOk

Manila

Vddivia

Iaknu

* llumhof

N days 271-360 63.4

(141)

(116)

(93)

66.0

55.8

(50)

(43)

44.7

67.7

60.0

73.7

(36)

(31)

(25)

(19)

79.8

75.8

89.5

97.0

(178)

(153)

(133)

(133)

(YE)

btexica Dlmnp

days :*-no 70.7

g

67.1

70.4

565

WJ)

(125)

(115)

72.6

71.6

67.7

67.9

(64)

(74)

(65)

(56)

56.3

52.9

65.0

32.7

c-71)

w

w

(55)

43.8

77.0

79.5

82.0

(178)

(143)

(127)

(111)

48.3

53.7

69.6

26.9

(89)

(82)

(69)

(67)

53.5

70.2

74.0

79.0

(129)

(114)

(1W

(95)

54.8

66.3

58.8

63.0

(115)

(86)

(60)

03)

39.0

65.0

79.5

87.9

(41)

(40)

(39)

(33)

58.1

71.1

73.1

73.4

(86)

(16)

(67)

(64)

61.3

78.6

72.1

58.2

(75)

00)

(61)

05)

66.8

69.0

65.0

67.4

(220)

(203)

(183)

(172)

54.8

75.7

69.6

54.6

(115)

(107)

(102)

(99)

71.5

73.0

67.5

57.5

(172)

(163)

ww

(16w

diaries for andyrr

indicucd

life-tile

dkmuinutimNsr

70.2

(89) hxico.

12aunth

Period

Maumul Ruwlu

Rcznl

24.8

56.3

24.5

64.2

15.9

63.3

15.9

33.5

11.0

39.4

10.9

42.0

10.1

42.0

9.0

42.0

6.9

29.0

6.8

29.1

5.3

23.0

4.4

27.7

3.8

34.0

2.1

49.2

0.9

31.6

0.0

15.1

0.0

10.5

in paIwhue#

NOVEMBER 1989 VOL. 40 NO. 5

543

4.

& C an es m c

tion of

The possibility of a worsening of the vaginal bleeding patterns with time was further investigated by analyzing the sequences of clinically important bleeding patterns with a formal test for trend following the methods of Machin aal. (7). The analysis of these sequences is summarized in Table V where 'acceptable‘ patterns in a reference period are indicated by From this table it can be A and 'unacceptable' patterns by U. seen, for example, that 68 of 116 (55%) women who discontinue HRPll2 after one reference period experience unacceptable patterns, for those who discontinue the method after two reference periods,24 of 83 (29%) experience 'unacceptable' patterns in both reference periods. For those completing three and four reference periods,12 of 72 (17%) and 23 of 73 (3%),respectively,experience 'unacceptable' The patterns in all reference periods. corresponding figures for HRP102 are 58, 22, 2 and 3%, respectively. The formal statistical analysis suggests that women (in both contraceptive groups) who discontinue method use after two and three reference periods are experiencing worsening patterns. For those who complete all four reference periods, there is no suggestion of an overall change in patterns and time. Table VI shows the numbers and percentages of women who decide to continue using their contraceptive method after having experienced an 'acceptable' or an 'unacceptable' vaginal bleeding pattern in the preceding reference period. Such data is not available for reference period IV since women who had completed the study were not given the choice to continue using these contraceptives. The table indicates that the experience of 'unacceptable‘ pattern in the immediately preceding reference period affects the discontinuation rate by 7 to 12%, and this observation is confirmed at the end of each reference period and for both drugs.

1.

Clinical trial

In 17 centres, 2320 women were randomly assigned to one of two once-a-month injectable preparations, HRPll2 or HRP102. Twothousand (86%) of them filled in a menstrual diary thus providing one of the largest menstrual bleeding data sets for a single study. Their analysis following the reference period method and the classification into vaginal bleeding patterns failed to identify any difference between the two formulations. With both preparations, there is a marked decrease in the incidence of bleeding and spotting after the first reference This reflects the pharmacokinetics of both preparations period. which contain each a progestogen and an estrogen (8). For both, the progestogen serum level rises to reach a peak 3 to 5 days after injection then decreases slowly until the next injection is given. By contrast the estrogen is shorter-acting. The serum

NOVEMBER 1989 VOL. 40 NO. 5

CONTRACEPTION

Table V. Sequences of clinically importantbleeding patterns

ReferencePeriod(s)

sequencesof Putems

HRPllZ

HRPlOZ

I ONLY

A U

48 68

58 81

116

139

26 23 10 24

36 22 15 21

TOtOl IMdII ONLY

AA AU UA UU TOul

2S.E.) =&0.04)* I. II mdIU ONLY

AAA AAU AUA AUU UAA UAU UUA UUU

14 7 6 2 15 9 7 12

14 1 5 5 4 9 4 1

b(S.E) =-it22(0.03)**

53 2S.E.) = 0.75(0.03)**

201 65 48 28 42 17 19 22 106 44 26 23 25 27 14 23

208 74 46 33 48 26 20 22 85 29 23 17 27 22 9 24

TOM

AAAA AAAU AAUA AAUU AUAA AUAU AUUA AUUU UAAA UAAU UAUA UAUU UUAA UUAU UUUA uuuu TOhI

Total numberof dies * pco.05 ** pc 0.01

for analysis

(S.E.) =9i.O7,.04)

730 i(S.H) = -0.014(0.01) 1001

713 ii(S.E.) = O.OO(O.01) 999

-

519 194

21 26

JII

acceptable

unacceptable

42 30

553 213

521 203

(92.6) (87.1)

(94.2) (82.1)

51 43

586 216

36 41

acceptable

unacceptable

81

(84.3)

365

68

II

570 290

58

(91.5)

520

48

acceptable.

(95.1) (88.2)

(91.6) (83.2)

(9w (78.2)

continuers

Number(percentage)

Unacccpt&le

Number diswntinuers

I

Number (pexcentage) camtinuers

Number discontinuers

Reference Fkriod

HRP102

Vaginal bleeding pattem during last mferenceperiod

HRF’112

Table VI. Number (percentage) of continuers after experiencing unacceptable patterns in previous reference period

CONTRACEPTION level of exogenous estradiol peaks a few days after injection then decreases to reach baseline values some lo-15 days after injection in the case of estradiol cypionate, the estrogen contained in HRP112, and 7-12 days in the case of estradiol valerate, the estrogen in HRPlO2. This drop in estrogen is followed by an estrogen withdrawal-induced vaginal bleeding episode. Thus the woman experiences a shortened first menstrual cycle which is followed by other estrogen-withdrawal bleeds at approximately 30day intervals. This is the main reason for the difference between the vaginal bleeding patterns observed during the first reference period and those observed thereafter. The improvement in vaginal bleeding patterns between reference periods I and II is shown both by the reference period method and by the classification into clinically important patterns. During the first reference period, the median number of bleeding/spotting episodes is 4 and the median number of days of bleeding or spotting is 18. 43.3% of HRPllP users and 37.1% of HRPlOP users have an 'unacceptable' pattern. For half of them, this is an irregular bleeding pattern, others experience frequent or infrequent bleeding. After this first reference period, the vaginal bleeding pattern shows great regularity throughout the following nine months. During a period of 90 days, the median number of bleeding episodes is 3, and the median length of these episodes is 4.5 days. The median length of bleeding/spotting-free intervals varies between 19 and 20 days. This type of regular pattern is experienced by 65 to 70% of users. Among the other users, twofifths experience infrequent bleeding, two-fifths experience irregular bleeding and one-fifth has frequent bleeding. The extremes of amenorrhea and prolonged bleeding are rare, experienced only by 2 to 3% of all users. Overall the analysis does not reveal major trends in vaginal bleeding patterns with prolonged use of either preparation. These results are in marked contrast with those observed in users of depot-medroxyprogesterone acetate (DMPA) alone, the progestogen which is contained in HRPllP. In a previous clinical trial (9), the diaries of 575 women using 150 mg DMPA every three months were analyzed using the same methodology as adopted in this paper. The percentage of women experiencing an 'acceptable' pattern decreased from 11.7% in the first reference period to 3.6% in the fourth reference period. These figures compared with 56.7% and 65.9% for the same reference periods for users of HRP112 and 62.8% and 65.4% for users of HRP102. Another striking difference is seen in the incidence of go-day amenorrhea. Among DMPA users, this was experienced by 10.4% women in the first reference period, Comparable increasing to 46.5% by the fourth reference period. figures are 0.3 and 2.3% for HRP112 users and 0.2 and 2.0% for HRPlO2 users. There are no data available from controlled randomized clinical trial comparing the bleeding patterns induced by once-amonth injectable contraceptives to those induced by other methods of contraception. However, to place the present results in

NOVEMBER 1989 VOL. 40 NO. 5

547

perspective, data from several WHO clinical trials are combined with those of this study in Figure 2. The data from these other studies were limited to the diaries of women who continued method use for one year, thus they do no include the worst patterns They were also experienced during the first 90 days of use. analyzed using the reference period method and were published previously (10). The figure shows box-whisker plots of the number of bleeding/spotting days during the first 90 days of use of different contraceptive methods. It confirms that, during the first 3 months of use, the number of bleeding/spotting days induced by HRP112 or HPPlOP has a distribution narrower than that induced by DMPA and similar to that induced by the vaginal ring releasing 20 ug of levonorgestrel per 24h. However further conclusions cannot be drawn from such comparisons made on a single parameter. In general the reasons given by the women for discontinuing their contraceptive method are reflected in their diaries. For menstrual reasons, the diaries show vaginal bleeding patterns which support the women's descriptions. For non-medical reasons, the diaries resemble those of the women who completed the study. In addition, the analysis shows that, as suspected, the women with the worst patterns discontinue first and that the last three months of experience have the most influence in their decision to stop using the contraceptive method. It also confirms an observation made in previous clinical trials (9,ll) that the tolerance to vaginal bleeding pattern abnormalities varies greatly from centre to centre. This is a reflection of the different perceptions of menstruation in different cultures (12) as well as the effects of medical counselling and support in different centres. However the analysis also suggests that women might give reasons for discontinuation unrelated to bleeding, despite having experienced disturbances in vaginal bleeding patterns. Fortythree per cent of the women who gave non-bleeding-related reasons had an 'unacceptable' vaginal bleeding pattern during the three months preceding their discontinuation. Thus the degree of tolerance to abnormal vaginal bleeding patterns as well as the accuracy in reporting discontinuation reasons can result in an underestimation of the vaginal bleeding irregularities measured by life-table analysis of clinical trial data. Similar findings were reported from other studies (9,ll). 2.

Method

Of the 25 women discontinuing for 'amenorrhea', sixteen have a pattern classified as 'infrequent bleeding' by our analysis. This suggests that the tolerance to amenorrhea for these women is less than the go-day limit arbitrarily set for the purpose of the made in previous analysis, and confirms an observation publications (9,lO) regarding the classification into clinically important bleeding patterns.

548

NOVEMBER 1989 VOL. 40 NO. 5

5th

I I

Percentiles

I

20

I_

25th 5Mh 75th

I

10

I

0

I--

95th

r

1

FIG.

30

I

t J

,

2

I

Days

maximum

40

I

50

(Fdapted

from

ref.

10)

BOX-WHISKER PLOTS OF THE NUMBER OF BLEEDING/SPOTTING THE FIRST 90 DAYS OF USE OF SEVERAL CONTRACEPTIVE

LEGEND: : minimum

HRP 102

HRP 112

Progenogen-only iniectable : Depot-medroxy progesterone acetate 150 mg

Levonorgenrel-releasing vaginal ring

Cambilwd pill : Levcmorgestrel 150 pg/ ethinyl esttadiol 30 fig

Combined pill : Norethiierone acetate 1 mg/ethinyl estndiol 50 pg

Ovulation method

I

&I

I

I

70

DAYS DURING METHODS

I

314

284

722

140

I

I

WHO 8.810~1

80

90

164

n = 1001

” =

“=

II=

“=

n=

In addition 23% of the 137 women who discontinued for bleeding reasons, were classified as having an 'acceptable' vaginal bleeding pattern. These observations illustrate how the limits used to categorize bleeding patterns are arbitrary and suggest a third source of underestimation of the importance of vaginal bleeding irregularities with contraceptive use. REFERENCES 1.

WHO Expanded Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-Acting Systemic Agents for the Regulation of Fertility. Multinational comparative clinical evaluation of two longacting injectable contraceptive steroids: norethisterone oenanthate and medroxyprogesterone acetate. 1. Useeffectiveness. Contraception 15:513-533 (1977)

2.

WHO Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-Acting Systemic Agents for the Regulation of Fertility. Multinational comparative clinical evaluation of two longnorethisterone acting injectable contraceptive steroids: oenanthate and medroxyprogesterone acetate. 2. Bleeding patterns and side effects. Contraception 17:395-406 (1978)

3.

Hall PE. Long-acting injectable formulations. In: Fertility regulation today and tomorrow. Diczfalusy E and Bygdeman M (eds). Serono Symposia publications, Raven Press, N.Y. (1987) p. 119-141

4.

World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. A multicentred Phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection: I. Contraceptive efficacy and side effects. Contraception 37:1-20 (1988)

5.

Rodriguez G, Faundes-Latham A and Atkinson LE. An approach to the analysis of menstrual patterns in the critical evaluation of contraceptives. Stud. Fam. Plann. 7~42-51 (1976)

6.

World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction; The analysis of vaginal bleeding patterns induced by fertility regulating methods. Contraception 34:253-260 (1986)

7.

Machin D, Farley TMMF, Busca B, Campbell MJ and d'Arcangues Assessing changes in vaginal bleeding patterns in C. contracepting women. Contraception 38:165-179 (1988)

550

NOVEMBER 1989 VOL. 40 NO. 5

CONTRACEPTION

8.

Aedo AR, Landgren B-M, Johannisson E and Diczfalusy E. Pharmacokinetic and pharmacodynamic investigations with monthly injectable contraceptive preparations. Contraception 31:453-469 (1985)

9.

World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. A multicentred Phase III comparative clinical trial of depotmedroxyprogesterone acetate given three monthly at doses of 100 mg or 150 mg: II. Comparison of bleeding patterns. Contraception 35:591-610 (1987)

10

Belsey EM and Task Force on Long-Acting Systemic Agents for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction. World Health Organization. Vaginal bleeding patterns among women using one natural and eight hormonal methods of contraception. Contraception 38:181-206 (1988)

11

World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction, Task on Long-Acting Systemic Agents for Fertility Force intravaginal levonorgestrel Regulation. Microdose contraception: A multicentre clinical trial. IV. Bleeding patterns. Contraception (Submitted for publication)

12

Snowden R and Christian perceptions of menstruation.

NOVEMBER 1989 VOL. 40 NO. 5

B, editors. Patterns Croom Helm, London (1983)

and

551