A Phase III randomized controlled trial of oral dydrogesterone versus intravaginal progesterone gel for luteal phase support in in vitro fertilization (Lotus II): results from the Chinese mainland subpopulation

Figures & data

Figure 1. Patient disposition (CONSORT flow diagram). The Chinese mainland subpopulation is depicted in gray boxes. Data for the overall study population (in white boxes) were previously reported in [26]. Georg Griesinger et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial, Human Reproduction (2018) 33 (12): 2212-2221, doi: 10.1093/humrep/dey306. Reproduced and adapted by permission of Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. © The Author(s) 2018. All right reserved. This figure is not included under the Creative Commons license of this publication. For permissions, please email: [email protected]. OUP and the ESC are not responsible or in any way liable for the accuracy of the adaptation. Taylor & Francis Online is solely responsible for the adaptation in this publication/reprint. ^aDetermined by inclusion/exclusion criteria. ^bThree subjects in the oral dydrogesterone group were discontinued prior to embryo transfer due to study drug-related issues; these subjects were included in the FAS as failures. DYD: dydrogesterone; ET: embryo transfer; FAS: full analysis sample; IVF: in vitro fertilization; MVP: micronized vaginal progesterone; PPS: per-protocol sample.

Table 1. Subject demographics and baseline characteristics (FAS).

	Overall population^a			Chinese mainland subpopulation
	Oral DYD (N = 494)	MVP gel (N = 489)	All (N = 983)	Oral DYD (N = 114)	MVP gel (N = 108)	All (N = 222)
Mean age, years (SD)	31.8 (4.4)	31.6 (4.6)	31.7 (4.5)	29.9 (3.9)	29.8 (4)	29.9 (3.9)
Age category, n (%)
<35 years of age	348 (70.4)	344 (70.3)	692 (70.4)	98 (86)	92 (85.2)	190 (85.6)
≥35 years of age	146 (29.6)	145 (29.7)	291 (29.6)	16 (14)	16 (14.8)	32 (14.4)
Race or ethnicity, n (%)
Asian	250 (50.6)	237 (48.5)	487 (49.5)	114 (100)	108 (100)	222 (100)
Black	1 (0.2)	0 (0)	1 (0.1)	0 (0)	0 (0)	0 (0)
White	237 (48)	247 (50.5)	484 (49.2)	0 (0)	0 (0)	0 (0)
Other	6 (1.2)	5 (1)	11 (1.1)	0 (0)	0 (0)	0 (0)
Mean BMI, kg/m^2 (SD)	23.1 (3.1)	23.1 (3)	23.1 (3)	22 (2.2)	22.3 (2.5)	22.2 (2.3)
Prior treatment^b, n (%)	71 (14.4)	61 (12.5)	132 (13.4)	30 (26.3)	31 (28.7)	61 (27.5)

BMI: body mass index; DYD: dydrogesterone; FAS: full analysis sample; IVF: in vitro fertilization; MVP: micronized vaginal progesterone; SD: standard deviation.

^aData for the overall population were previously reported in [26]. Georg Griesinger et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial, Human Reproduction (2018) 33 (12): 2212–2221, doi: 10.1093/humrep/dey306. Reproduced and adapted by permission of Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. © The Author(s) 2018. All right reserved. This table is not included under the Creative Commons license of this publication. For permissions, please email: [e-mail]. OUP and the ESC are not responsible or in any way liable for the accuracy of the adaptation. Taylor & Francis Online is solely responsible for the adaptation in this publication/reprint.

^bPrior treatment included assisted fertilization, IVF, ovulation induction, and artificial insemination by partner or donor.

Figure 2. Pregnancy and live birth rates posttreatment (FAS). Pregnancy rates at 12 weeks of gestation, and live birth rates for the overall Lotus II population and the Chinese mainland subpopulation. A non-inferiority margin of 10% was used for the overall population, whereby the test drug is non-inferior if the lower bound of the 95% CI excludes a difference greater than −10%. Data for the overall population were previously reported in [26]. ^aAt 12 weeks of gestation. CI: confidence interval; DYD: dydrogesterone; FAS: full analysis sample; MVP: micronized vaginal progesterone.

Table 2. Course and outcomes of pregnancy (FAS).

	Overall population^a			Chinese mainland subpopulation
	Oral DYD	MVP gel	All	Oral DYD	MVP gel	All
Subjects who underwent ET, N	491^b	489	980	114	108	222
Subjects who underwent ET after ICSI, n (%)	321 (65.4)	304 (62.2)	625 (63.8)	40 (35.1)	28 (25.9)	68 (30.6)
Day of ET after OR, n (%)
<5 days	319 (65)	286 (58.5)	605 (61.7)	104 (91.2)	98 (90.7)	202 (91)
≥5 days	172 (35)	203 (41.5)	375 (38.3)	10 (8.8)	10 (9.3)	20 (9)
Number of embryos transferred, n (%)
1	162 (33)	164 (33.5)	326 (33.3)	26 (22.8)	23 (21.3)	49 (22.1)
2	324 (66)	324 (66.3)	648 (66.1)	87 (76.3)	85 (78.7)	172 (77.5)
>2	5 (1)	1 (0.2)	6 (0.6)	1 (0.9)	0 (0)	1 (0.5)
Total number of newborns, n	205	188	393	84	65	149
Subjects who had at least one newborn, n (%)	170 (34.6)	159 (32.5)	329 (33.6)	61 (53.5)	51 (47.2)	112 (50.5)
One newborn infant, n (%)	135 (79.4)	131 (82.4)	266 (80.9)	38 (62.3)	37 (72.5)	75 (67)
Two newborn infants, n (%)	35 (20.6)	27 (17)	62 (18.8)	23 (37.7)	14 (27.5)	37 (33)
More than two newborn infants, n (%)	0 (0)	1 (0.6)	1 (0.3)	0 (0)	0 (0)	0 (0)
Multiple birth, %	20.6	17.6	19.1	37.7	27.5	33
Weight, kg (mean ± SD)	2.9 ± 0.7	3 ± 0.7	3 ± 0.7	2.8 ± 0.7	2.9 ± 0.7	2.9 ± 0.7

DYD: dydrogesterone; ET: embryo transfer; FAS: full analysis sample; ICSI: intracytoplasmic sperm injection; MVP: micronized vaginal progesterone; OR: oocyte retrieval; SD: standard deviation.

^aData for the overall population were previously reported in [26].

Georg Griesinger et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial, Human Reproduction (2018) 33 (12): 2212–2221, doi: 10.1093/humrep/dey306. Reproduced and adapted by permission of Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

© The Author(s) 2018. All right reserved. This table is not included under the Creative Commons license of this publication. For permissions, please email: [e-mail]. OUP and the ESC are not responsible or in any way liable for the accuracy of the adaptation. Taylor & Francis Online is solely responsible for the adaptation in this publication/reprint.

^bThree subjects in the oral dydrogesterone group were discontinued prior to embryo transfer.

Table 3. Maternal TEAEs (safety sample).

	Overall population^a			Chinese mainland subpopulation
	Oral DYD (N = 518)	MVP gel (N = 512)	All (N = 1030)	Oral DYD (N = 119)	MVP gel (N = 119)	All (N = 238)
Maternal TEAEs, n^b (%)
All TEAEs	275 (53.1)	249 (48.6)	524 (50.9)	87 (73.1)	69 (58)	156 (65.5)
At least one TESAE	71 (13.7)	67 (13.1)	138 (13.4)	28 (23.5)	31 (26.1)	59 (24.8)
At least one severe TEAE	38 (7.3)	35 (6.8)	73 (7.1)	8 (6.7)	16 (13.4)	24 (10.1)
At least one TEAE leading to study termination	64 (12.4)	57 (11.1)	121 (11.7)	13 (10.9)	17 (14.3)	30 (12.6)
Maternal death	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Reproductive system and breast disorders	89 (17.2)	82 (16)	171 (16.6)	42 (35.3)	34 (28.6)	76 (31.9)
Vaginal hemorrhage	51 (9.8)	37 (7.2)	88 (8.5)	26 (21.8)	13 (10.9)	39 (16.4)
Ovarian hyperstimulation syndrome	21 (4.1)	21 (4.1)	42 (4.1)	9 (7.6)	15 (12.6)	24 (10.1)
Vulvovaginal signs and symptoms	11 (2.1)	9 (1.8)	20 (1.9)	8 (6.7)	3 (2.5)	11 (4.6)
Vaginal discharge	11 (2.1)	3 (0.6)	14 (1.4)	8 (6.7)	2 (1.7)	10 (4.2)
Vulvovaginal discomfort	0 (0)	4 (0.8)	4 (0.4)	0 (0)	0 (0)	0 (0)
Vulvovaginal pruritus	1 (0.2)	2 (0.4)	3 (0.3)	1 (0.8)	1 (0.8)	2 (0.8)
Gastrointestinal disorders	69 (13.3)	67 (13.1)	136 (13.2)	20 (16.8)	14 (11.8)	34 (14.3)
Liver function analyses	7 (1.4)	8 (1.6)	15 (1.5)	4 (3.4)	5 (4.2)	9 (3.8)
ALT increased	2 (0.4)	4 (0.8)	6 (0.6)	1 (0.8)	3 (2.5)	4 (1.7)
AST increased	2 (0.4)	3 (0.6)	5 (0.5)	1 (0.8)	3 (2.5)	4 (1.7)
Transaminases abnormal	1 (0.2)	0 (0)	1 (0.1)	1 (0.8)	0 (0)	1 (0.4)
Hepatic enzyme increase	2 (0.4)	2 (0.4)	4 (0.4)	1 (0.8)	1 (0.8)	2 (0.8)
GGT increased	0 (0)	2 (0.4)	2 (0.2)	0 (0)	1 (0.8)	1 (0.4)
Blood bilirubin decreased	1 (0.2)	0 (0)	1 (0.1)	1 (0.8)	0 (0)	1 (0.4)
Blood bilirubin increased	1 (0.2)	0 (0)	1 (0.1)	0 (0)	0 (0)	0 (0)
Nervous system disorders	19 (3.7)	19 (3.7)	38 (3.7)	2 (1.7)	1 (0.8)	3 (1.3)
Vascular disorders	12 (2.3)	9 (1.8)	21 (2)	1 (0.8)	0 (0)	1 (0.4)
Peripheral embolism and thrombosis	1 (0.2)	1 (0.2)	2 (0.2)	1 (0.8)	0 (0)	1 (0.4)

N = number of subjects in safety sample.

n = number of subjects with TEAEs.

ALT: alanine aminotransferase; AST: aspartate aminotransferase; DYD: dydrogesterone; GGT: gamma-glutamyltransferase; MVP: micronized vaginal progesterone; TEAE: treatment-emergent adverse event; TESAE: treatment-emergent serious adverse event.

^aData for some of the parameters in the overall population were previously reported in [26].

^bSubjects may have more than one TEAE.

Table 4. Fetal/neonatal population TEAEs.

	Overall population^a			Chinese mainland subpopulation
	Oral DYD (N = 221)	MVP gel (N = 201)	All (N = 422)	Oral DYD (N = 87)	MVP gel (N = 71)	All (N = 158)
Congenital, familial, and genetic disorders, n^b (%)	14 (6.3)	10 (5)	24 (5.7)	4 (4.6)	9 (12.7)	13 (8.2)
Atrial septal defect	5 (2.3)	7 (3.5)	12 (2.8)	2 (2.3)	6 (8.5)	8 (5.1)
Heart disease congenital	2 (0.9)	4 (2)	6 (1.4)	2 (2.3)	4 (5.6)	6 (3.8)
Patent ductus arteriosus	1 (0.5)	4 (2)	5 (1.2)	0 (0)	4 (5.6)	4 (2.5)
Congenital aortic anomaly	0 (0)	1 (0.5)	1 (0.2)	0 (0)	1 (1.4)	1 (0.6)
Accessory auricle	1 (0.5)	0 (0)	1 (0.2)	0 (0)	0 (0)	0 (0)
Amniotic band syndrome	1 (0.5)	0 (0)	1 (0.2)	0 (0)	0 (0)	0 (0)
Congenital central nervous system anomaly	1 (0.5)	0 (0)	1 (0.2)	1 (1.1)	0 (0)	1 (0.6)
Congenital cystic kidney disease	1 (0.5)	0 (0)	1 (0.2)	0 (0)	0 (0)	0 (0)
Congenital hand malformation	1 (0.5)	0 (0)	1 (0.2)	1 (1.1)	0 (0)	1 (0.6)
Cystic lymphangioma	1 (0.5)	0 (0)	1 (0.2)	1 (1.1)	0 (0)	1 (0.6)
Intestinal malrotation	1 (0.5)	0 (0)	1 (0.2)	0 (0)	0 (0)	0 (0)
Kinematic imbalance due to occipital strain	1 (0.5)	0 (0)	1 (0.2)	0 (0)	0 (0)	0 (0)
Renal dysplasia	1 (0.5)	0 (0)	1 (0.2)	0 (0)	0 (0)	0 (0)
Turner’s syndrome	1 (0.5)	0 (0)	1 (0.2)	0 (0)	0 (0)	0 (0)

N = overall number of fetuses/newborns.

n = number of fetuses/newborns with anomalies.

DYD: dydrogesterone; MVP: micronized vaginal progesterone; TEAE: treatment-emergent adverse event.

^aData for the overall population were previously reported in [26].

Georg Griesinger et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial, Human Reproduction (2018) 33 (12): 2212–2221, doi: 10.1093/humrep/dey306. Reproduced and adapted by permission of Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

© The Author(s) 2018. All right reserved. This table is not included under the Creative Commons license of this publication. For permissions, please email: [e-mail]. OUP and the ESC are not responsible or in any way liable for the accuracy of the adaptation. Taylor & Francis Online is solely responsible for the adaptation in this publication/reprint.

^bFetuses/newborns may have more than one anomaly.

Griesinger G, Blockeel C, Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in in vitro fertilization: a randomized clinical trial. Hum Reprod. 2018;33:2212–2221.

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Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.