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CTRI Number  CTRI/2021/05/033815 [Registered on: 25/05/2021] Trial Registered Prospectively
Last Modified On: 13/05/2021
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Process of Care Changes 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   Comparative study of effectiveness of follicular monitoring in the first cycle of successful ovulation following treatment with letrozole versus regular follicular monitoring in every cycle of letrozole therapy in infertile females with polycystic ovarian syndrome (PCOS). 
Scientific Title of Study   Comparative study of effectiveness of index cycle monitoring versus regular follicular monitoring in infertile females with polycystic ovarian syndrome (PCOS) undergoing ovulation induction with letrozole. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Sujata Pradhan 
Designation  Professor 
Affiliation  Center for Human Reproduction, Institute of Medical Sciences and SUM Hospital, Bhubaneswar 
Address  Center for Human Reproduction, Department of Obstetrics & Gynaecology Room no-5 Institute of Medical Sciences and SUM hospital, K8 Kalinga Nagar, Bhubaneswar

Khordha
ORISSA
751003
India 
Phone  9437262488  
Fax    
Email  dr.suzzane@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Sujata Pradhan 
Designation  Professor 
Affiliation  Center for Human Reproduction, Institute of Medical Sciences and SUM Hospital, Bhubaneswar 
Address  Center for Human Reproduction,Department of Obstetrics & Gynaecology, Room no-5 Institute of Medical Sciences and SUM hospital, K8 Kalinga Nagar, Bhubaneswar

Khordha
ORISSA
751003
India 
Phone  9437262488  
Fax    
Email  dr.suzzane@gmail.com  
 
Details of Contact Person
Public Query  
Name  Sujata Pradhan 
Designation  Professor 
Affiliation  Center for Human Reproduction, Institute of Medical Sciences and SUM Hospital, Bhubaneswar 
Address  Center for Human Reproduction,Department of Obstetrics & Gynaecology, Room no-5 Institute of Medical Sciences and SUM hospital, K8 Kalinga Nagar, Bhubaneswar

Khordha
ORISSA
751003
India 
Phone  9437262488  
Fax    
Email  dr.suzzane@gmail.com  
 
Source of Monetary or Material Support  
Institute of medical sciences& Sum Hospital 
 
Primary Sponsor  
Name  Institute of Medical Sciences Sum Hospital 
Address  K8 kalinga Nagar,Bhubaneswar Dist-Khorda State-Odisha Pin-751003 
Type of Sponsor  Private medical college 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Sujata Pradhan  Institute of Medical Sciences and SUM Hospital  Center for Human Reproduction,Department of Obstetrics & Gynaecology(Room no-5) , K8, Kalinga Nagar, Bhubaneswar 751003
Khordha
ORISSA 		 9437262488

dr.suzzane@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institutional Ethics Committee, Institute of Medical Sciences (IMS) and SUM Hospital, Siksha O Anusandhan (Deemed to be University)  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: N970||Female infertility associated withanovulation, (2) ICD-10 Condition: N970||Female infertility associated withanovulation,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Index cycle monitering  Patients will be advised to take the prescribed dose of letrozole with which optimal follicular response is achieved for 5 days starting on Days 3 – 5of menstrual cycle for 2 more cycles.They will be advised for intercourse every alternate day from 10th to 20th day of menstrual cycle without further follicular monitoring during this period.These patients will be provided a self cycle monitoring and drug administration proforma and instructed to fill it after each treatment cycle.Urine pregnancy test at home will be advised to be performed if cycle is delayed by 7 days. They will be advised for follow up at the end of two domiciliary treatment cycles or a positive urine pregnancy test whichever is earlier.  
Comparator Agent  Regular follicular monitoring  Patients will be planned for ovulation induction with the prescribed dose of letrozole with which an optimal follicular response was achieved.The treatment will be continued for two more cycles or a positive urine pregnancy test whichever is earlier. These patients will be advised for ultrasonographic follicular monitoring every cycle at our centre.Urine pregnancy test is advised 20 days after a positive follicular response in ultrasonography. 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  37.00 Year(s)
Gender  Female 
Details  1. Infertile females with PCOS diagnosed as per Rotterdam criteria
2. Treatment naive patients without prior history of ovulation induction
3. Normal to mild male factor(sperm concentration >10 million /ml)
 
 
ExclusionCriteria 
Details  1. Patients with the previous history of ovulation induction
2. Moderate to severe male factor.
3. Females with bilateral tubal block, endometriosis, pelvic inflammatory disease.
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Sequentially numbered, sealed, opaque envelopes 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Clinical Pregnancy - Ultrasound confirmation of pregnancy at 7 weeks of gestation  Clinical Pregnancy - Ultrasound confirmation of pregnancy at 7 weeks of gestation 
 
Secondary Outcome  
Outcome  TimePoints 
1. Positive urine pregnancy test
2. Number of hospital visits to achieve pregnancy
3. Cycle regularity
4. Incidence of multiple pregnancies 		 1. After 7 days of missed menstrual cycle
2. 7 week of gestation
3. After 7 days of missed menstrual cycle
4. 7 week of gestation 
 
Target Sample Size   Total Sample Size="130"
Sample Size from India="130" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   N/A 
Date of First Enrollment (India)   08/06/2021 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="2"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   Nil 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary  

Project proposal

1.      Methodology:Infertile females withPCOS diagnosed as per Rotterdam criteria will be considered for the study.Patientssatisfying the inclusion andexclusion criteria will be planned for ovulation induction with letrozole. The minimum dose of letrozole will be 2.5mg daily for five days starting on 3rd to5th dayof menstrual cycle. The patients will be advised to come for follicular monitoring 7 – 8days after the last dose of letrozole.Follicular monitoring will be done by transvaginal ultrasonography using a probe of frequency 5-9MHz.Presence of one or  two dominant follicles of size ≥15 mmin ultrasonography will be considered as  optimal follicular response and that cycle will be regarded as the index cycle. Patients with dominant follicle size of 13 – 15mm will be considered to have suboptimal response. These patients will be excluded from the study &will be called for repeat scan within a week.Absence of a leading follicle of size > 13 mm will be regarded as non-response.In case of non -response,the dose of letrozole will be increased by 2.5mg every cycle up to a maximum dose of 7.5mg.Patients who fail to ovulate with the highest daily dose of letrozole(7.5mg) will be excluded from the study.If she develops more than two dominant follicles of ≥ 15mm, the cycle will be cancelled in view of hyper response and the couple will be advised to avoid unprotected intercourse for 10 days.Recruitment will be done for the patients with a positive follicular response through transvaginal ultrasonography.Participants will be randomly allocated into two groups after obtaining writteninformed consentbased on the type of monitoring i.e. Index cycle (group A) and regular monitoring (group B). Randomization will be done by computer generated random number sequence. In the first group (Group A),patients will be advised to take thesame  dose with which optimal follicular response is achieved for 5 days starting on Days 3 – 5of menstrual cycle for 2 more cycles.They will be advised for intercourse every alternate day from 10th to 20th day of menstrual cycle without further follicular monitoring during this period.These patients will be provided a self cycle monitoring and drug administration proforma and instructed to fill it after each treatment cycle.Urine pregnancy test at home will be advised to be performed if cycle is delayed by 7 days.  They will be advised for follow up at the end of two domiciliary treatment cycles or a positive urine pregnancy test whichever is earlier. Patients allocated to group B will be planned for ovulation induction with the same dose of letrozole with which an optimal follicular response was achieved.The treatment will be continued for two more cycles or a positive urine pregnancy test whichever is earlier. These patients will be advised for ultrasonographic follicular monitoring every cycle at our centre.Urine pregnancy test is advised 20 days after a positive follicular response in ultrasonography.

Inclusion criteria:  

 

Infertile females with PCOS diagnosed as per Rotterdam criteria between 18-37 years of age,without prior history of ovulation induction with normal to mild male factor( sperm concentration >10 million /ml) will be considered for the study.

 

Exclusion criteria:

Females with bilateral tubal block, endometriosis,pelvic inflammatory disease,moderate to severe male factor will be excluded from the study.

2.      Sample Size:Taking into consideration of 70% success ratefollowing induction by Letrozole and a clinically acceptable margin 20% between the experimental and control group for non-inferiority trial with a alpha of 5% and power of 80%, the sample size was calculated to be 130 with 65 in each group (allocation ratio 1:1)(7).

3.      Study duration: 2 years

4.      Primary Outcome:

Clinical pregnancy as defined by ultrasonographic confirmation of pregnancy at 7 weeks gestational age will be considered as the primary outcome.

5.      Secondary outcomes:

Positive urine pregnancy test, cycle regularity,incidence of multiple pregnancies and  number of hospital visits to achieve pregnancy

will be considered as secondary outcomes.

 

6.      Probable outcome: Pregnancy rate is expected to be similar in regular follicular monitoring as well as index cycle monitoring after ovulation induction with letrozole.

7.      Novelty of the study:To best of our knowledge, the current study will be the first study of to delineate the effectiveness of index cycle monitoring versus regular monitoring in infertile females with letrozole induced ovulation.

8.      Ethical concern & how to overcome:

Conventionally patients are advised for ultrasonographic follicular monitoring every cycle after taking letrozole. If this study demonstrates similar pregnancy rate, definitely patients will be benefited with less number of hospital visits, lesser financial burden. Simultaneously work burden of the clinics will also be reduced. Since we have planned to recruit patients after observing an ideal follicular response in the index cycle, the possibility of suboptimal or hyper response with the samedose of letrozole will be ruled out in subsequent cycles.

Current routine clinical practice will be followed, and patients will not be subjected to extra burden or risk.Written informed consent will be taken from the participants after explaining the basis of the study and confidentiality will be maintained .

9.      References:

[1]    Helena J Teede, Marie L Misso, Michael F Costello, AnujaDokras, JoopLaven, Lisa Moran, TerhiPiltonen, Robert J Norman, International PCOS Network, Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome, Human Reproduction, Volume 33, Issue 9, September 2018, Pages 1602–1618,

[2]   Amer SA, Smith J, Mahran A, Fox P, Fakis A. Double-blind randomized controlled trial of letrozole versus clomiphene citrate in sub-fertile women with polycystic ovarian syndrome. Hum Reprod2017; 32(8):1631-1638.

 

[3]   Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P,Christman GM, Huang H, Yan Q, Alvero R et al. Letrozole versus clomiphenefor infertility in the polycystic ovary syndrome. N Engl J Med 2014 ,10:119–129.

[4]   Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer. 2002;95:2006–2016. 

[5]   Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. FertilSteril 2015;103:e44–50

[6]   Munro MG, Critchley HOD, Fraser IS, Committee FMD. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J GynecolObstet 2018, 143(3): 393–408

[7]   Zhong Baoliang, How to calculate sample size in randomized controlled trial?. J Thorac Dis 2009; 1(1): 51-54



 
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