A phase 1, multicentre, open-label study to evaluate ovarian follicular activity and hormone levels with an extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation

Figures & data

Figure 1 Study flow diagram (TVU, transvaginal ultrasound).

Table 1 Ovarian Activity Grading System.²⁰

		Follicle-like structure	Hormones
Grading of ovarian activity		Size mm	Estradiol nmol/L	Progesterone nmol/L
0	No activity	≤ 10
1	Potential activity	> 10
2	Non-active FLS	> 13	≤ 0.1
3	Active FLS	> 13	> 0.1	≤ 5
4	LUF	> 13, persisting	> 0.1	> 5
5	“Ovulation”	> 13, ruptured*	> 0.1	> 5

FLS, follicle-like structure; LUF, luteinized unruptured follicle.

Adapted from Hoogland HJ and Skouby SO, Ultrasound evaluation of ovarian activity under oral contraceptive. Contraception 1993;47:583–90, adapted with permission from the Association of Reproductive Health Professionals and the Society of Family Planning.

*Grade 5 was distinguished from Grade 4 by follicle rupture, defined as the disappearance of the follicle or a decrease in maximum follicular diameter by 50% within 2 to 4 days.

Table 2 Demographics and other baseline characteristics.

Parameter	ITT cohort (n = 43)	Efficacy cohort (n = 35)
Race, n (%)
African American	6 (14.0%)	6 (17.1%)
Asian	2 (4.7%)	2 (5.7%)
Caucasian	32 (74.4%)	25 (71.4%)
Other	3 (7.0%)	2 (5.7%)
Age, mean (SD), y	26.96 (3.90)	27.60 (3.75)
BMI, mean (SD), kg/m^2	23.14 (3.25)	23.39 (3.14)
Systolic blood pressure, mean (SD), mm Hg	104.05 (9.96)	104.97 (10.25)
Diastolic blood pressure, mean (SD), mm Hg	65.16 (5.92)	65.43 (6.28)
Heart rate, mean (SD), beats/min	69.79 (8.01)	70.26 (8.34)

BMI, body mass index; ITT, intent to treat; SD, standard deviation.

Table 3 Ovarian activity rates (cycle level) for the 91-day treatment cycle converted into three cycle-based intervals of 28 to 35 days: Efficacy cohort.

Ovarian Activity Grade*	Interval 1 (28 days) [35 subject cycles]		Interval 2 (28 days) [35 subject cycles]		Interval 3 (35 days) [35 subject cycles]		Total (91 days) [105 subject cycles]
	n	%	n	%	n	%	n	%
0 – No activity	20	57.14	31	88.57	31	88.57	82	78.10
1 – Potential activity	6	17.14	1	2.86	1	2.86	8	7.62
2 – Non-active FLS	0	0.00	2	5.71	1	2.86	3	2.86
3 – Active FLS	9	25.71	0	0.00	0	0.00	9	8.57
4 – LUF	0	0.00	0	0.00	0	0.00	0	0.00
5 – Ovulation	0	0.00	1	2.86	2	5.71	3‡	2.86
Ovarian activity rate^†	0	0.00	1	2.86	2	5.71	3^‡	2.86
90% CI		0.00, 8.2		0.15, 12.85		1.02, 16.92		0.78, 7.22

n, number of subject cycles; CI, confidence interval; FLS, follicle-like structure; LUF, luteinized unruptured follicle.

*Only the most significant ovarian activity grade was used for subject cycles in each cycle-based interval.

^†Includes subjects who experienced LUF (grade 4) and ovulation (grade 5).

^‡One subject demonstrated a grade 5 score in cycle-based intervals 2 and 3.

Figure 2 Mean serum progesterone (PGN) levels during 91-day treatment period.

Figure 3 Mean serum 17β-estradiol (E2) levels during 91-day treatment period.

Figure 4 Mean serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels during 91-day treatment period.

Table 4 Proportion of subjects who returned to ovulation during the post-treatment cycle.

	Efficacy cohort (n = 35)			ITT cohort (n = 43)
Ovulation status	n	%	95% CI^†	n^‡	%	95% CI
Returned to ovulation*	27	77.14	59.86, 89.58	33	78.57	63.19, 89.70
Did not ovulate	8	22.86	10.42, 40.14	9	21.43	10.30, 36.81

CI, confidence interval; ITT, intent to treat.

*If progesterone (PGN) ≥ 15.9 nmol/L was not obtained at final study visit (cycle-day 18, 19, or 20 of post-treatment cycle), then PGN concentrations were measured up to 6 times total on a Monday, Wednesday, Friday schedule until a value of ≥ 15.9 nmol/L was reached or a period of 12 days had elapsed since initial assessment.

^†95% confidence interval is based on the exact Clopper-Pearson method.

^‡One subject discontinued due to an adverse event.

Hoogland HJ, Skouby SO. Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 1993;47:583–90.

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