Clinical trial NCT02821819
Conditions: Infertility
Keywords: ovarian stimulation random egg donation antagonist gnrh agonist trigger
Sponsor: Instituto Bernabeu
Start date: 2017-01-10; Completion date: 2018-01-12
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this prospective single-center study is to evaluate the laboratory outcome after random start ovarian stimulation in oocyte donors. The study will be performed in egg-donors but this type of treatment has the potential to be implemented in general infertility population.

Detailed description:
The study group will start ovarian stimulation randomly in different moments throughout the menstrual cycle.

Randomization will take place on day 2-3 of the menstrual cycle, according to a list of random allocation of treatments and egg-donors will be assigned to random start ovarian stimulation: During follicular phase starting at day 5,7,9,11 or 13 of the menstrual cycle and during luteal phase starting at luteinizing hormone (LH) peak +3,+5,+7,+9 or +11.

Egg-donors will receive urinary follicle stimulating hormone (FSH) 150-225 IU/d in gonadotropin-releasing hormone (GnRH) antagonist protocol with cetrorelix acetate 0,25 mg/d starting five days after ovarian stimulation and a GnRH agonist trigger with triptorelin 0,2 mg to induce the final follicular maturation. Transvaginal ultrasound and serum analysis (estradiol, progesterone, LH and FSH) will be included for cycle monitoring.

Arms: arm 1: Egg-donors will be assigned to random start ovarian stimulation: During follicular phase starting at day 5,7,9,11 or 13 of the menstrual cycle and during luteal phase at luteinizing hormone (LH) peak +3,+5,+7,+9 or +11. They will receive urinary follicle stimulating hormone (FSH) 150-225 International units / daily (IU/d) and five days later the gonadotropin-releasing hormone (GnRH) antagonist: cetrorelix acetate 0,25 mg/d will be added until achieving criteria for receiving triptorelin 0,2 mg to induce final follicular maturation. Egg collection will take place 36 hours later.

Interventions:

* Random start ovarian stimulation
* Gonadotrophins: Urinary FSH 150-225 IU/d
* GnRH antagonists: Cetrorelix 0,25 mg/d
* GnRH agonist for triggering: Triptorelin 0,2 mg single dose
Interventions: intervention 1: Random start ovarian stimulation intervention 2: Gonadotrophins intervention 3: GnRH antagonist intervention 4: GnRH agonist
Intervention descriptions: intervention 1: Egg-donors will start ovarian stimulation randomly at different moments throughout the menstrual cycle. intervention 2: Urinary FSH 150-225 IU/d intervention 3: Cetrorelix acetate 0,25 mg/d starting five days after ovarian stimulation intervention 4: GnRH agonist triggering with triptorelin 0,2 mg for final follicular maturation.

Protocol documents:
Prot_SAP_000.pdf: 
COVER PAGE 
 
 
 
Official Title: 
Random-start Ovarian Stimulation in Egg-donors (ROSE) Trial: a Self-controlled Pilot 
Study 
NCT number: 02821819 
Date: February 03th 2019 
 
 


STUDY PROTOCOL 
 
1. Scientific background 
Random-start ovarian stimulation (OS) cycles have been well described in oncologic 
patients for female fertility preservation. In this scenario, (usually) young women have 
initiated ovarian stimulation independently of the menstrual cycle following an specific 
ovarian stimulation protocol (1) 
Recently, Kuang et al. (2) showed that it was feasible to perform a “lutheal phase” 
stimulation or even two consecutive ovarian stimulations in the same cycles (the so-
called “DUOSTIM” protocol). This “luteal” phase stimulation protocol has been also 
described in egg-donors in a pilot trial (3). Importantly, in egg-donors, luteal phase 
stimulation seems to provide competent eggs. 
The physiologic fundamentals for the optimal results in these “non-conventional” 
stimulation protocol is derived from the “follicular waves” theory described by 
Baerwald et. al. (4). 
Of notice, random-start stimulation protocols initiating in the mid/to late follicular 
phase have been essentially in the oncologic population and, so far, optimal results are 
described (5-6). The same optimal results have been also described in luteal phase 
stimulation protocols, nonetheless, at least one study has related luteal phase 
stimulation protocol with suboptimal results in terms of pregnancy achievement (7).  
The current trial aims to explore the concept of random-start stimulation protocols, 
namely, initiating ovarian stimulation on the mid/late follicular and luteal phase and to 
compare the results versus conventional stimulation protocols initiating OS in the early 
follicular phase in the egg-donor population. This approach might facilitate schedules 
in egg-donor IVF programs. 
 
2. Methods 
2.1 Design  
This is a prospective, open, randomized, self-comparative, pilot study. The type of 
protocol (antagonist/GnRH-a trigger) and gonadotrophin type/dose will be identical 
between the study and control groups; except for the day of starting the OS process in 
relation to the last menses. The control cycle includes a conventional previous cycle 
underwent by the same population in the six previous months of the randomization, 
thereby, decreasing inter-subject variability. The eggs from the study group will be 


inseminated using IVF conventional / ICSI using partner´s sperm. Fertilization will be 
evaluated 18-24 hours later. 
 
2.2 Study population 
a) Inclusion criteria: 
• Egg-donors having at least one previous ovarian stimulation for egg-donation in 
our institution within the six months before being enrolled in the current trial. 
• Regular cycles 27 +- 7 days 
• Written / signed informed consent. 
 
b) Exclusion criteria: 
• Ovarian pathology at the moment of initiating COS (e.g ovarian cysts)  
• Simultaneous participation in another study.  
 
2.3 Objectives 
a) Main outcome 
• Total number of collected eggs 
• Total number of metaphase II eggs 
• Proportion of metaphase II eggs: total number/number of metaphase II 
B) Secondary outcomes 
• To evaluate the total number of days for COS 
•  
• To evaluate the amount of gonadotrophin consumption (IU) 
2.4 Statistical analysis plan and sample size  
The sample size was calculated assuming a non-inferiority margin of 5 eggs SD 6.7 
(based on: Devroey et al. Hum Reprod. 2009;24(12):3063-72). A unilateral alpha level 
of 0.05 was stablished. With the aim to show that the difference in the mean number 
of collected eggs will not exceed 5, a statistical power of 80% required 30 patients per 
group (1:1 allocation, total sample: 60). Statistical analysis was performed using t-
student test for continuous variables and chi-square test for categorical parameters. A 
P value of <.05 was considered significant. 
 


STUDY PROTOCOL OVERVIEW 
 
Visit: 
Schedule 
Investigation: 
Visit 0 
(pre-study) 
30 days prior to starting 
Controlled Ovarian Stimullation 
 Verification of inclusion criteria  
 Informed consent form  
Visit 1 
From day 1º - 3º of the cycle for 
ovarian stimulation  
 Signature of informed consent  
 Blood simple for Estradiol levels 
 Vaginal scan and follicular count  
 Height and weight  
 Randomization 
 
STUDY GROUP: 
Visit: 
Schedule  
Investigation: 
Start of 
treatment 
(S1) 
Beginning of gonadotrophins 
administration (according to 
randomization):  
- 
5º day of the cycle  
- 
7º day of the cycle 
- 
9º day of the cycle 
- 
11º day of the cycle 
- 
13º day of the cycle 
 Starting dose: identical to the dose used in the 
control cycle.  
 S1 refers to the first day of ovarian stimulation  
Visit 2 
(1st control) 
On the 5º-6º of ovarian 
stimulation (S5-S6) 
 Transvaginal scan and folliculometry 
 Starting of GnRH antagonist (Cetrotide® ) 
 Blood samples: Estradiol, Progesterone, FSH, LH 
Follow-up 
Every 24-72 hours  
 Transvaginal scan and folliculometry 
Visit 3 
(Agonist) 
On the day of triggering (final 
follicular maturation) 
 Transvaginal scan and folliculometry 
 Administration of 2 ampules of Decapeptyl® (0,2 mg 
triptorelin acetate) with follicles 18-20 mm. 
Visit 4 
(Egg 
collection) 
Egg collection 
 Transvaginal egg retrieval 36 hours after triggering. 
 Blood samples: Estradiol, Progesterone, FSH, LH. 
 
CONTROL GROUP: 
A previous cycle underwent by the egg-donor within 6 months previously to the 
inclusion in the study group for the ROSE trial; in brief: 


• Day 1-2 of the cycle. Transvaginal scan and follicular count. Starting of 
gonadotrophins 150-225 IU (Fostipur®) according to BMI and AFC (D1 of 
ovarian stimulation). 
• Day 5-6 of ovarian stimulation. Transvaginal scan and folliculometry. Starting of 
GnRH antagonists (Cetrotide®) beginning with a dominant follicle ≥ 14 mm. 
• Follow-up every 24-72 hours. 
• Administration of 2 ampules of Decapeptyl® (0,2 mg triptorelin acetate) with 
follicles 18-20 mm to induce the final follicular maturation. 
• Transvaginal egg retrieval 36 hours after triggering 
 
Main outcome 
To evaluate and compare the total number and MII rate of eggs collected after 
beginning the ovarian stimulation in different moments of the follicular phase vs 
standard protocol. 
 
Secondary outcomes 
To evaluate differences with regards to the duration of the ovarian stimulation, FSH 
consumption and fertilization rates between groups.