Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction.
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ABSTRACT:
SUBMITTER: Yland JJ
PROVIDER: S-EPMC8971650 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
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Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction.
Yland Jennifer J JJ Chiu Yu-Han YH Rinaudo Paolo P Hsu John J Hernán Miguel A MA Hernández-Díaz Sonia S
Human reproduction (Oxford, England) 20220401 4
<h4>Study question</h4>What are the comparative pregnancy outcomes in women who receive up to six consecutive cycles of ovulation induction with letrozole versus clomiphene citrate?<h4>Summary answer</h4>The risks of pregnancy, livebirth, multiple gestation, preterm birth, neonatal intensive care unit (NICU) admission and congenital malformations were higher for letrozole compared with clomiphene in participants with polycystic ovarian syndrome (PCOS), though no treatment differences were observ ...[more]
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Project description:BackgroundThe aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile women with ovulatory dysfunction.MethodsA randomized controlled trial was conducted at a single academic medical center between November 2020 and December 2021. Anovulatory infertility females, aged 18 to 40, were evenly distributed by a computer-generated block of four into two treatment groups. A "combination group" received a daily dose of CC (50 mg) and letrozole (2.5 mg), while a "CC-alone group" received a daily dose of CC alone (50 mg). The study medications were administered on days 3 through 7 of menstrual cycle. The primary outcome was the ovulation rate, defined by serum progesterone levels exceeding 3 ng/mL at the mid-luteal phase. The secondary outcomes were ovulation induction cycle characteristics, endometrial thickness, conception rate, and adverse events.ResultsOne hundred women (50 per group) were enrolled in the study. The mean age was not significantly different in both groups: 31.8 years in the combination group and 32.4 years in the CC-alone groups (P = 0.54). The prevalence of polycystic ovary syndrome in the combination and CC-alone groups was 48% and 44%, respectively (P = 0.841). According to intention-to-treat analysis, the ovulation rates were 78% and 70% in the combination and CC-alone groups, respectively (P > 0.05). There was no significant difference in the mean endometrial thickness or the number of dominant follicles of the groups. No serious adverse events were observed in either group.ConclusionsOur study found no significant difference between the combination of CC and letrozole and CC alone in inducing ovulation in infertile women with ovulatory dysfunction in one cycle. The small number of live births precluded any meaningful statistical analysis. Further studies are needed to validate and extend our findings beyond the scope of the current study.Trial registrationThe study was registered at https://www.thaiclinicaltrials.org with the following number: TCTR20201108004 and was approved on 08/11/2020.
| S-EPMC10647029 | biostudies-literature
Project description:ObjectivesTo compare the efficacy of letrozole (LTZ) vs clomiphene citrate (CC) for ovulation induction in patients having polycystic ovarian syndrome (PCOS).MethodsThis randomized controlled trial was conducted at The Department of Obstetrics & Gynecology, Nishtar Medical University Hospital, Multan, Pakistan from January 2021 to June 2021. A total of 78 women aged 18 to 30 years, diagnosed having PCOS were enrolled. In Group-A, 39 women were given LTZ, 5mg for five days of menstrual cycle. In Group-B, 39 women were given CC, 100mg for five days of menstrual cycle. All patients underwent transvaginal scan (TVS) for the evaluation of efficacy in terms of ovulation induction.ResultsOverall mean age was noted to be 25.41±2.84 years. Most of the patients, 51 (65.4%) belonged to rural area of residence. There were 52 (66.7%) patients with BMI less than 25 kg/m2. Overall, mean duration of infertility was found to be 2.62±0.74 years. Among 70 patients who completed the follow ups and analyzed regarding efficacy, in Group-A, efficacy was noted in 23 (59.0%) patients in comparison to 14 (35.9%) in Group-B (p=0.0413). Mean endometrial thickness was significantly better in Group-A versus Group-B (8.1±1.5 mm vs. 6.8±1.9 mm, p=0.0022).ConclusionAiming ovulation induction, letrozole in comparison to clomiphene citrate was found to have significantly better efficacy among women having anovulatory PCOS.
| S-EPMC9247780 | biostudies-literature
Project description:ObjectiveTo compare the efficacy of letrozole vs Clomiphene citrate for ovulation induction in PCOS women.MethodsThis double blind randomized controlled trial was conducted at Services Hospital, Lahore, from January 2016 to December 2020. Total 220 patients, diagnosed with PCOS according to Rotterdam criteria were randomly assigned into two groups after taking informed consent. The women were followed for ovulation, pregnancy and live birth rates in the next five consecutive menstrual cycles with either clomiphene citrate or letrozole.ResultsLetrozole had significantly better pregnancy rate (29.0% vs 15.4% p-value 0.015), monofollicular development (77.2% vs 52.7% p-value 0.000) and live birth rate (25.4% vs 10.9% p-value 0.005) as compared to clomiphene citrate. There was no difference between the two groups in ovulation rate (68.1% vs 63.6%, p-value 0.477), early pregnancy loss (3.6% vs 4.5% p-value 0.734), and twin pregnancy (0.0% vs 1.81% p-value 0.155). There was no ectopic pregnancy and no congenital anomalies in both groups. Hot flushes were higher in clomiphene group (31.8% vs 12.7% p-value 0.001) while fatigue (30.9% vs 8.1% p-value 0.000) and dizziness (21.8% vs 10.0% p-value 0.029) was higher with letrozole but these were well tolerated.ConclusionLetrozole is better treatment choice than clomiphene citrate in PCOS women with infertility in terms of pregnancy and live birth rate.ClinicalTrials.gov Identifier: NCT05702957.
| S-EPMC10772410 | biostudies-literature
Project description:The comparative efficacies of ovulation-induction treatments in patients with clomiphene citrate-resistant (CCR) polycystic ovary syndrome (PCOS) are not well known. Therefore, we conducted a network meta-analysis to rank the reproductive efficacies of these treatments. We ultimately included 26 randomized clinical trials with 2722 participants and 9 types of therapies: clomiphene citrate (CC), metformin, letrozole, follicle stimulating hormone (FSH), human menopausal gonadotropin (hMG), unilateral laparoscopic ovarian drilling (ULOD), bilateral laparoscopic ovarian drilling (BLOD), the combination of metformin with letrozole (metformin+letrozole), and the combination of metformin with CC (metformin+CC). The network meta-analysis demonstrates that hMG therapy result in higher pregnancy rates than BLOD, ULOD and CC therapies. Pregnancy, live birth and ovulation rates are significantly higher in metformin+letrozole and FSH groups than CC group. The abortion rate in the metformin+letrozole group is significantly lower than that in the metformin+CC group. Ranking probabilities show that, apart from gonadotropin (FSH and hMG), metformin+letrozole is also potentially more effective in improving reproductive outcomes than other therapies. In conclusion, owing to the low quality of evidence and the wide confidence intervals, no recommendation could be made for the treatment of ovulation-induction in patients with CCR PCOS.
| S-EPMC5476620 | biostudies-literature
Project description:BackgroundThe purpose of this study was to assess the effect of combining low dose of Coenzyme Q10 with clomiphene citrate on ovulation induction in polycystic ovary syndrome (PCOS) women with clomiphene resistance.MethodsA total of 149 women with clomiphene resistant PCOS who needed ovulation induction were randomly allocated to oral clomiphene citrate and Coenzyme Q10 group and oral clomiphene citrate only group using a computer generated allocation sequence. The study was conducted at Aziz Medical Center, Karachi, Pakistan from 1st July 2020 to 1st October 2020. Polycystic ovary syndrome was diagnosed according to Rotterdam criteria. The primary outcome was ovulation and conception rate per cycle. Chi square test and Fischer's exact test were used to compare these variables at p<0.05 level of significance.ResultsOf the 133 women assessed, the proportion of women who ovulated with combination (70% vs., 19%, p=0.001) was greater and the combination group had greater conception rate per cycle than those who received only clomiphene (48.6% vs. 6.3%, p<0.001). When stratified according to obesity, 85.3% of non-obese women who received combination ovulated whereas only 55.6% of obese women ovulated (p=0.002). Moreover, 48.6% of non-obese women conceived in the combination group as compared to 6.3% of obese women (p=0.007). Women who received combination were six times more likely to conceive than women who only received clomiphene citrate (AOR=6.344, 95% CI: 1.452-27.71, p=0.014).ConclusionCoenzyme Q10 is a valuable adjunct in women with PCOS undergoing ovulation induction. It improves ovulation and conception in women with clomiphene resistance.
| S-EPMC9666598 | biostudies-literature
Project description: Not available
| S-EPMC5850470 | biostudies-literature
Project description:OBJECTIVE: To evaluate the benefit of Metformin added to Clomiphene Citrate in a primary ovulation induction protocol in PCOS patients. DESIGN: Prospective randomised controlled study. SETTING: Tygerberg Academic Hospital, Stellenbosch University and the Institute of Reproductive Medicine at Vincent Pallotti Hospital, Cape Town. PATIENTS: 107 patients presenting with PCOS. STUDY: Group A was pre-treated with metformin 850 mg twice a day for at least 6 weeks before clomiphene was added and the metformin was used throughout the study period. Group B received clomiphene without pre-treatment with metformin. In both groups clomiphene was given at a starting dose of 50 mg day 4-8 and increase with increments of 50 mg to a maximum of 150 mg if no response was achieved. RESULTS: The ovulation rate achieved in women in the M+C/C arm was 34/52 (65.4%) compared to 36/55 (65.5%) in the C/C arm. The treatment effect ((M+C/C) - C/C) is 0% with 95% confidence interval of -18.1% to 18%. The per protocol ovulation results were 34/42 (81%) in the M+C/C arm compared to 36/48 (75%) in the C/C arm. The ovulation rate difference was 6% with 95% confidence interval -11% to 22%. In a comparison of successful ovulating versus non-ovulating women from the trial the following were significant baseline determinants: lower median weight in the ovulating group (77 kg versus 86 kg, p = .021), lower median bmi (29.0 versus 32.9, p = .009), lower median DHEAS at baseline (4.6 compared to 7.0, p = .049), lower median 17OH-progesterone (2.2 versus 4.6, p = .027) and higher baseline median SHBG ( 37.8 compared to 28.5, p = .036). CONCLUSION: Although identical ovulation rates were observed in both arms equivalence could not be concluded with respect to the specified criteria.
| S-EPMC2682185 | biostudies-other
Project description:BackgroundThe aim of this randomized controlled trial was to compare the efficacy of extended letrozole regimen with clomiphene citrate in women with unexplained infertility undergoing superovulation and intrauterine insemination (IUI).MethodsTwo hundred and fourteen patients with unexplained infertility were randomized into two equal groups using computer generated list and were treated by either letrozole 2.5 mg/day from cycle day 1 to 9 (extended letrozole group, 211 cycles) or clomiphene citrate 100 mg/day from cycle day 3 to 7 (clomiphene citrate group,210 cycles). Intrauterine insemination was performed 36 to 40 hours after HCG administration.ResultsBoth groups were comparable with regard to number of mature follicles (2.24 +/- 0.80 Vs 2.13 +/- 0.76) and the day of HCG administration. Serum estradiol was significantly greater in clomiphene citrate group (356 +/- 151 Vs 822 +/- 302 pg/ml, P = < 0.001) and the endometrial thickness was significantly greater in extended letrozole group (9.10 +/- 1.84 Vs 8.18 +/- 1.93 mm, P = < 0.001).The pregnancy rate per cycle and cumulative pregnancy rate were significantly greater in extended letrozole group (18.96% Vs 11.43% and 37.73% Vs 22.86%, respectively).ConclusionThe extended letrozole regimen had a superior efficacy as compared with clomiphene citrate in patients of unexplained infertility undergoing superovulation and IUI.Trial registrationClinicalTrials.gov, NCT01232075.
| S-EPMC3135532 | biostudies-literature
Project description:BackgroundAlthough a recent study reported that the pregnancy outcomes in the first trimester were more correlated with endometrial thickness on the day of the trigger than with endometrial thickness on the day of single fresh-cleaved embryo transfer, it remains unclear whether endometrial thickness on the day of the trigger can predict live birth rate after a single fresh-cleaved embryo transfer.ObjectiveThis study aimed to examine whether endometrial thickness on the trigger day is associated with live birth rates and whether modifying the single fresh-cleaved embryo transfer criteria to reflect endometrial thickness on the trigger day improved the live birth rate and reduced maternal complications in a clomiphene citrate-based minimal stimulation cycle.Study designThis was a retrospective study of the outcomes of 4440 treatment cycles of women who underwent single fresh-cleaved embryo transfer on day 2 of the retrieval cycle. From November 2018 to October 2019, single fresh-cleaved embryo transfer was performed when endometrial thickness on the day of single fresh-cleaved embryo transfer was ≥8 mm (criterion A). From November 2019 to August 2020, single fresh-cleaved embryo transfer was conducted when endometrial thickness on the day of the trigger was ≥7 mm (criterion B).ResultsA multivariate logistic regression analysis revealed that increased endometrial thickness on the trigger day was significantly associated with an improvement in the live birth rate after single fresh-cleaved embryo transfer (adjusted odds ratio, 1.098; 95% confidence interval, 1.021-1.179). The live birth rate was significantly higher in the criterion B group than in the criterion A group (22.9% and 19.1%, respectively; P=.0281). Although endometrial thickness on the day of single fresh-cleaved embryo transfer was sufficient, the live birth rate tended to be lower when endometrial thickness on the trigger day was <7.0 mm than when endometrial thickness on the day of the trigger was ≥7.0 mm. The risk for placenta previa was reduced in the criterion B group when compared with the criterion A group (4.3% and 0.6%, respectively; P=.0222).ConclusionThis study demonstrated an association of decreased endometrial thickness on the trigger day with low birth rate and a high incidence of placenta previa. A modification of the criteria for a single fresh-cleaved embryo transfer based on endometrial thickness may improve pregnancy and maternal outcomes.
| S-EPMC9975686 | biostudies-literature
Project description:ObjectiveTo emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A1c (HbA1c).DesignObservational study.SettingOptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019.ParticipantsAdults with type 2 diabetes and HbA1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine.Main outcome measuresThe primary outcome was time to HbA1c ≥7.0%. Secondary outcomes were time to HbA1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression.Results8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes.ConclusionsIn this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.
| S-EPMC9527635 | biostudies-literature