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ORIGINAL RESEARCH |
From the Beth Israel Deaconess Medical Center, Boston, Massachusetts; and the Ortho-McNeil Pharmaceutical Corporation, Raritan, New Jersey.
Address reprint requests to: Ann Davis, MD, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215
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Abstract |
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Methods: In this multicenter, randomized, double-masked study, 201 women (15–50 years of age) with DUB received triphasic norgestimate-ethinyl E2 or placebo, for three consecutive 28-day treatment cycles. Efficacy was determined by evaluating investigator and subject assessments of DUB resolution, abnormal uterine bleeding patterns during an 84-day reference period, and change from baseline in subjects’ quality of life. The sample size was based on the assumption that the proportions of subjects exhibiting treatment success (percentage of subjects with investigator and subject overall assessments of DUB resolution of "improved") were 65% for the active group and 40% for the placebo group (
= 0.05, 1 - ß = 0.80).
Results: More than 80% of subjects receiving triphasic norgestimate-ethinyl E2 had improvements in their abnormal bleeding patterns as assessed by investigators, and the subjects themselves compared with fewer than 50% of subjects in the placebo treatment group (P < .001). Abnormal bleeding patterns were reported by significantly fewer subjects receiving triphasic norgestimate-ethinyl E2 than in the placebo treatment group (P < .001). Change from baseline in physical functioning (eg, self-care, walking, lifting, exercising) was significantly more improved in the triphasic norgestimate-ethinyl E2 group than in the placebo group.
Conclusion: The triphasic combination of norgestimate and ethinyl E2 is an effective treatment for metrorrhagic, menometrorrhagic, oligomenorrheic, and polymenorrheic dysfunctional uterine bleeding.
Abnormal uterine bleeding is a significant medical problem and accounts for up to 33% of outpatient gynecologic visits annually.1 Patterns of abnormal bleeding are numerous and may have organic or functional causes. The term dysfunctional uterine bleeding (DUB) is used to describe abnormal uterine bleeding with no organic cause (ie, bleeding from the endometrium unrelated to anatomic lesions of the uterus). Dysfunctional uterine bleeding is usually a diagnosis of exclusion, and is applied when organic or structural causes of abnormal uterine bleeding have been ruled out. The majority of cases of DUB are related to the disruption of normal ovarian function and consequent failure to ovulate. It is characterized by irregular bleeding episodes that vary in amount and duration of bleeding. The treatment goals of DUB are to control acute bleeding and to manage the chronic conditions.2
Exogenous steroids are the most common treatments used in women with DUB. Progestins such as medroxyprogesterone acetate, megestrol acetate norethindrone, norethindrone acetate, and depot medroxyprogesterone acetate are prescribed in differing regimens as part of DUB therapy. Combination oral contraceptives (OCs) are also frequently used.3–5 Medical opinion and experience indicate that combination OCs are effective treatments for DUB; however, well-controlled trials designed to study their efficacy, particularly in subjects with anovulatory DUB, have not been reported.
Triphasic norgestimate-ethinyl E2 is a triphasic combination of norgestimate and ethinyl E2 approved for contraception and for the treatment of moderate acne. Norgestimate is a gonane progestin with negligible androgenic activity. Triphasic norgestimate, in combination with 35 µg ethinyl E2, is safe and effective and has an excellent tolerability profile.6–8 Because well-established regular bleeding patterns are exhibited by users of this OC, this product is a suitable choice for study.
This article presents results from a randomized, double-masked, placebo-controlled, multicenter study to evaluate the efficacy of the combination triphasic OC norgestimate-ethinyl E2 in the treatment of metrorrhagic, menometrorrhagic, oligomenorrheic, or polymenorrheic DUB, conditions usually associated with anovulation.
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Materials and Methods |
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All eligible subjects provided informed consent, were between 15 and 50 years of age; in good general health, not pregnant or nursing, and had at least a 2-month history of metrorrhagic, menometrorrhagic, oligomenorrheic, or polymenorrheic DUB that was not attributable to systemic disease or structural pathology. Women with a history of endometrial ablation and those who had undergone dilatation and curettage within 90 days before the screening visit were excluded. The use of nonsteroidal anti-inflammatory drugs and medications that could affect OC metabolism were prohibited during the study period.
The study design is given in Figure 1
. During screening, subjects underwent physical and gynecologic examinations and a serum pregnancy test, and their medical history (including menstrual history) was recorded. Documentation of a recent episode of abnormal bleeding was also required. Tests of coagulation, thyroid, prolactin, FSH, LH, testosterone, and sex hormone binding globulin were performed to rule out functional causes of DUB. Vaginal sonography with saline infusion or hysteroscopy procedures were performed in subjects over 30 years of age to identify and rule out anatomic lesions. Blood pressure (BP) and body weight were recorded and hematologic (hemoglobin and hematocrit), and serum chemistry tests were obtained. Endometrial biopsies and mammograms (if the subject had not had a mammogram during the previous 2 years) were performed on subjects over 40 years of age, or when clinically indicated.
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The admission visit took place after the investigator received all screening test results. After the quality-of-life survey was administered, subjects were assigned to treatment or placebo using a computer-generated randomization schedule (Ortho-McNeil Pharmaceutical, Raritan, NJ). The study drug was also packaged at Ortho-McNeil Pharmaceutical, in individual, sealed, subject-numbered boxes, according to the randomization schedule. A set of subject-numbered boxes (eg, 100–110) was forwarded to each investigator at study initiation. Upon meeting the entrance criteria, and in strict sequential order, each subject was assigned the next available number by the investigator or designate. The drug inside this numbered box (also identically numbered) was then dispensed to the subject. All boxes and tablet dispensers were identical, with the exception of subject number. For each of the three 28-day treatment cycles, subjects assigned to treatment received the following daily doses: days 1–7, 0.180 mg norgestimate/0.035 mg ethinyl E2; days 8–14, 0.215 mg norgestimate/0.035 mg ethinyl E2; days 15–21, 0.250 mg norgestimate/0.035 mg ethinyl E2; and days 22–28, inactive tablets. Subjects randomized to placebo treatment received identical placebo tablets. Subjects were counseled to use a nonsteroidal method of birth control (except an intrauterine device) for the duration of the study. Condoms were distributed as needed. For symptomatic relief of headaches or pain during the 84-day study period, acetaminophen was provided because of the nonsteroidal anti-inflammatory drug exclusion. Subjects started treatment on the day following the last day of a bleeding/spotting episode.
Follow-up visits were scheduled after each cycle to assess safety and compliance. An investigator’s overall assessment of DUB resolution, a subject’s self-assessment of the change in DUB from baseline, and a repeat of the quality-of-life survey were collected at the end of the study. To avoid physician influence, subjects completed the quality-of-life survey and the self-assessment of the change in their DUB before meeting with the investigator.
The primary efficacy variables were the investigator’s overall assessment score of the resolution of the subject’s DUB (excellent, good, fair, no change, worse, unable to evaluate) and the subject’s self-assessment score (much improved, improved, slightly improved, no change, worse, don’t know). The secondary efficacy variables included abnormal uterine bleeding patterns during the 84-day reference period and an evaluation of the change from baseline in quality-of-life scores at the final visit. The 84-day reference period analysis included an evaluation of the presence or absence of abnormal bleeding patterns and, more specifically, the frequency. This modified reference period analysis was based on the methods of Belsey, et al10 but was altered for use in this trial. Regularity of uterine bleeding patterns was defined as the absence of clinically important abnormal bleeding patterns. These patterns were derived from the subjects’ bleeding diaries. The clinically important abnormal bleeding patterns during the 84-day reference period are listed in Table 1. The quality-of-life evaluations were based upon the expanded Medical Outcome Study, 36-item, short-form health survey that measures generic health concepts across age, disease, and treatment groups.11 In addition to the 36 items in the original short-form health survey, five items from the full set of Medical Outcome Study questions were added for deriving a sexual functioning scale. Safety was assessed through elicited and volunteered reports of adverse events, measurement of systolic and diastolic BP, and laboratory analysis of serum hemoglobin concentrations and serum hematocrit during the study.
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The efficacy analyses were performed on three separate data sets: the intent-to-treat population (subjects who took at least one dose of study therapy), the evaluable-for-efficacy population (subjects who completed the study, had no major protocol violations, and were compliant overall [did not miss two consecutive pills or three or more pills during any of the three cycles]), and the reference-period-analysis population (subjects from the evaluable-for-efficacy population who had no missing bleeding/spotting data during the 84-day reference period and who started study medication on a bleed-free day).
The primary efficacy analysis was based on the intent-to-treat population. The Cochran-Mantel-Haenszel 
2 test, controlling for centers, was used to compare the distributions of investigator and subject assessment scores between the two treatment groups.
Two-sided tests were used to evaluate differences between the two treatment groups in secondary efficacy variables and to assess treatment-by-center interactions. For all quality-of-life scales, analysis of covariance was applied to assess the effect of therapy on the respective health outcomes, after adjusting for baseline score, study centers, and interaction terms. In all cases, P < .05 was considered statistically significant. Investigators, study staff, subjects, and data analysts remained masked to group assignment until the study was completed and the database was locked. Evaluability determinations were conducted before the mask was broken. No interim analysis was planned or performed. All analyses reported were included in the original protocol plan, except of the investigator and subject assessments that were analyzed by a pre-study abnormal bleeding pattern subgroup.
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Results |
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Demographic and baseline characteristics for the intent-to-treat population are given in Table 2. In the intent-to-treat population, subjects in the treatment group and the placebo group were similar with respect to baseline demographic parameters, including duration of abnormal bleeding and bleeding pattern history. In general, the demographic and baseline characteristics of the evaluable-for-efficacy and reference-period populations were similar to those for the intent-to-treat population.
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and 3, respectively. The distributions of investigator assessment were significantly different between the treatment and placebo groups (P < .001). In the treatment group, overall investigator assessments of improvements were more than twofold greater than those in the placebo group (81.4% compared with 35.8%). The most common investigator rating in the treatment group was excellent (41.2% compared with 10.5% in the placebo group). The most common investigator rating in the placebo group was no change (46.3% compared with 10.3% in the treatment group).
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The distributions of investigator and subject assessments at the end of treatment were similar in the intent-to-treat populations for each of the four prestudy bleeding pattern population subgroups (metrorrhagia, menometrorrhagia, oligomenorrhea, and polymenorrhea).
The number and percentage of subjects with regular and abnormal bleeding patterns during the 84-day reference period for the reference-period-analysis population are given in Table 3. The incidence of abnormal bleeding was significantly less in the treatment group compared with the placebo group for the reference-period-analysis population (P < .001). In the treatment group, 53.3% of the subjects reported abnormal bleeding patterns compared with 90.6% of subjects in the placebo group. Each abnormal bleeding pattern was reported by fewer subjects in the treatment group than in the placebo group with the exception of prolonged bleeding, which occurred more frequently in the treatment group. Infrequent bleeding was reported by notably fewer subjects in the treatment group compared with the placebo group (8.3% compared with 53.1%).
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The mean change from baseline in quality-of-life scores for the intent-to-treat population is given in Table 4. The quality-of-life scores at the end of the study were more favorable in the treatment group than in the placebo group in all categories except health transition. The mean change from baseline scores was comparable between treatment groups in all categories except physical functioning, in which the magnitude of improvement was significantly greater in the treatment group compared with the placebo group (4.19 compared with 0.47, P < .001).
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Discussion |
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This clinical study was designed to examine the efficacy of a triphasic OC containing norgestimate and 35 µg of ethinyl E2 in the treatment of anovulatory DUB.
Overall, triphasic norgestimate-ethinyl E2 was well tolerated and was significantly more effective than placebo in the treatment of DUB. Analysis of the primary efficacy outcome variables—the investigator’s overall assessment of the resolution of the subject’s DUB and the subject’s self-assessment score—showed a statistically significant improvement in treated subjects compared with placebo controls. Furthermore, the distributions of investigators’ and subjects’ assessments within the subgroup strata determined by the prestudy abnormal bleeding patterns (metrorrhagia, menometrorrhagia, oligomenorrhea, and polymenorrhea) showed similar differences between the treatment groups. These analyses support the effectiveness of triphasic norgestimate/ethinyl E2 for the treatment of different DUB subgroups.
The substantial percentages of improved placebo subjects in the investigators’ and subjects’ assessment (35.8% and 45.3%, respectively) illustrate the expected placebo effect in this trial. Because of the irregularity and unpredictability of DUB, subjects may have irregular bleeding one month and regular bleeding the next. Therefore, either by chance alone or by placebo effect, subjects receiving placebo could report improvement or resolution of DUB.
The investigator’s overall assessment of DUB resolution and the subject’s self-assessment score were established as primary endpoints because more objective measures that quantitate change in DUB are difficult to define. Normalization of menstrual bleeding patterns (ie, regular 28-to-35 day cycles lasting less than 7 days) may result from different quantitative and qualitative changes in baseline bleeding patterns, depending on the specific DUB subgroups. For instance, women with polymenorrhea will improve if they bleed less frequently as their cycles become more regular, whereas women with oligomenorrhea will bleed more often when their cycles normalize. The definition of improvement in DUB therefore varies for these two subgroups. In an attempt to objectively measure regular cycles, a modified reference period analysis was designed to determine presence and absence of abnormal bleeding and the frequency of abnormal uterine bleeding patterns.
The results of this reference period analysis of abnormal uterine bleeding patterns supported the results of the primary efficacy measures. A significantly higher proportion of women who took placebo had at least one episode of abnormal bleeding compared with treated subjects (90.6% compared with 53.3%, P < .001). It is possible that some episodes of abnormal bleeding reported by treatment users occurred before a treatment effect was established, or were episodes of breakthrough bleeding. The strict definition of a bleeding/spotting episode (ie, at least 1 day of bleeding/spotting) may have contributed to the relatively high proportion of subjects in both groups labeled as having abnormal bleeding. The difference between groups in terms of the number of women with prolonged bleeding (16 treated versus 10 placebo) was not statistically significant (P = .185). Unfortunately, further analysis is prohibited by the small number of women overall with this type of bleeding pattern.
Descriptively, greater improvements in quality-of-life scores were observed in the treatment group compared with the placebo group. These differences, however, were statistically significant for physical functioning. The physical functioning health concept of the survey instrument is designed to evaluate the extent to which health limits and affects physical activities such as self-care, walking, climbing stairs, bending, lifting, and moderate and vigorous exercise. In fact, of all concepts tested, this item is perhaps the quality-of-life change most expected to improve during active treatment.
Maintaining the mask for subjects and investigators in this trial was extremely important because of the subjective nature of the primary endpoints. The relatively short duration of the study may be the primary reason for the low percentage of early discontinuations (17.4%). This small percentage of dropouts was, in general, uniformly divided between the groups (15.8% in the treatment group and 19% in the placebo group). These low and similar discontinuation rates between the groups may support effective maintenance of the mask. Although there were slightly higher numbers of treatment subjects than placebo subjects reporting breast pain and nausea, the number of subjects reporting other events commonly attributable to OC use (eg, headache and weight gain) was not different between the groups. The overall number of reports of each event was low in the sample population of 201 women. Therefore, the likelihood is very small that the occurrence of such events compromised the mask. Even if one assumed that the mask was broken during the study and the findings of the investigators’ and subjects’ assessments were discounted, the objective measures of the reference period analysis remain, to support the effectiveness of treatment over placebo.
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Footnotes |
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The authors thank the participating investigators: Samuel Christian, MD; Jay Cooper, MD; Wayne Coxwell, MD; Ann Davis, MD; Catherine Dean, MD, MPH; Sidney Funk, MD; Dorothy Skye, MD; George Schade, MD; Barbara Soltes, MD; H. Hutson Messer, MD; Joseph Bellina, MD; R. Lamar Parker, Jr., MD; Ray Wolff, MD; Donald Edger, MD; Marjorie Merod, MD; and Royal Benson III, MD.
Financial Disclosure
Author Davis was a paid investigator and her institution, Beth Israel Deaconess Medical Center, received payment from Ortho-McNeil Pharmaceutical Corporation for conducting the study. Authors Godwin, Lippman, Olson, and Kafrissen are employees of Ortho-McNeil.
Received February 22, 2000. Received in revised form May 16, 2000. Accepted June 1, 2000.
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References |
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2. Bayer SR, DeCherney AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993;269:1823–8.[Abstract]
3. Wathen RI, Henderson MC, Witz CA. Abnormal uterine bleeding. Med Clin North Am 1995;79:329–42.[Medline]
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5. Chen BH, Giudice LC. Dysfunctional uterine bleeding. West J Med 1998;169:280–4.[Medline]
6. Corson SL. Efficacy and safety of a monophasic and a triphasic oral contraceptive containing norgestimate. Am J Obstet Gynecol 1994; 170:1556–61.[Medline]
7. Andolsek KM. Cycle control with triphasic norgestimate and ethinyl estradiol, a new oral contraceptive agent. Acta Obstet Gynecol Scand 1992;71(Suppl. 156):22–6.[Medline]
8. Gauthier A, Upmalis D, Dain M. Clinical evaluation of a new triphasic oral contraceptive: Norgestimate and ethinyl estradiol. Acta Obstet Gynecol Scand 1992;71(Suppl. 156):27–32.
9. Higham JM, O’Brien PMS, Shaw RW. Assessments of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990;97: 734–9.[Medline]
10. Belsey EM, Machin D, d’Arcangues C. The analysis of vaginal bleeding patterns induced by fertility regulating methods. Contraception 1986;34:253–60.[Medline]
11. Ware JE, Snow KK, Kosinski M, Gandek B. SF–36 health survey manual and interpretation guide (Medical outcomes study, Medical Outcomes Trust). Boston: The Health Institute, New England Medical Center, 1993.
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