Outcome of Cetrotide Therapy for Management of Women at High-risk of Ovarian Hyperstimulation Syndrome

Phase 2

Conditions: Infertility

Interventions: Drug: Cetrorelix

Registration Number: NCT02823080

Lead Sponsor: Benha University

Brief Summary: To evaluate safety and efficacy of 3-day cetrotide therapy started on day of oocyte retrieval (Day-0) in women at high-risk for development of ovarian hyperstimulation syndrome (OHSS) after gonadotropin- releasing hormon agonist induction protocol.

Patients \& Methods: Forty-eight women fulfilling inclusion criteria underwent ultrasound scanning for maximal ovarian diameter (MOD) estimation and ascites grading. Patients underwent embryo freezing, but study group received 3-day Cetrotide sc injection (0.25 mg/day) started on Day-0. Serum E2, pain scores and MOD were checked daily. Hematocrit value (Ht%), total leucocytic count (TLC), gastrointestinal (GI) manifestations and ascites grading were re-evaluated on Day-3, 6 and 8

Detailed Description: The current study is conducted at Assisted Reproduction Unit at Almana general Hospital, kingdom of saudi arabia.and other private centers in Egypt. The study protocol was approved by the Local Ethical Committee. The study aimed to include women suspected to be at high risk for development of OHSS during agonist ovarian stimulation protocol.The study includes only women of couples singed written consent to participate in the study, to undergo embryo freezing and to postpone for transfer of cryopreserved embryo.

All patients are clinically evaluated for the presence of abdominal pain and if present will be graduated using a numerical pain visual analogue scale (VAS) with 0 means no pain and 10 means severe intolerable pain. Patients are evaluated for the presence of nausea and/or vomiting and sense of abdominal distension. Symptoms are scored using verbal analogue scale as nil, mild, moderate, and severe symptom. Blood samples are obtained under complete aseptic condition for estimation of serum E2 level and determination of hematocrit value (Ht%) and total leucocytic count (TLC).

Then, all patients underwent ultrasound scanning for estimation of ovarian measurements that were represented as the maximal ovarian diameter (MOD) and for ascites grading if present. Ultrasound scanning is performed using a 5 megahertz vaginal probe , otherwise a 3.5 megahertz, 2.6 megahertz or 5megahertz abdominal probe is used if visualization using a vaginal probe is compromised. Ascites is graded according to the quantity of fluid accumulation in the peritoneal cavity with the patient in the anti-Trendelenburg position.

Women fulfilling inclusion criteria were randomely allocated,using sealed envelops, into two equal groups. Group with embryo freezing alone (Control group) or while the other group additionally receives cetrotide subcutaneous injection in a daily dose of 0.25 mg started on day of oocyte retrieval for 3 days (Study group). Symptomatic treatment for associated symptoms as analgesics, antiemetics and antispasmodics are also prescribed. Patients are categorized according to classification grading of OHSS.

Class Clinical features Biochemical features

Mild - Abdominal distension/ discomfort

* Mild nausea/vomiting

* Diarrhea

* Ovarian size usually \< 8 cm No clinically important laboratory findings

Moderate - Mild features plus

* US evidence of ascites - Elevated Ht (\>41%)

* Elevated TLC \>15,000/ ml

* Hypoproteinemia

Severe - Mild \& Moderate features plus

* Clinically detected ascites

* Severe abdominal pain

* Intractable nausea

* Rapid weight gain (\>1 kg/24 hr)

* Pleural effusion

* Severe dyspnea

* Oliguria/anuria

* Low blood/central venous pressures

* Syncope

* Venous thrombosis

* Hemoconcentration (Ht \>55%)

* TLC \>25,000/ ml

* Serum creatinine \>1.6 mg/dl

* creatinine clearance \<50 ml/min

* Hyponatremia (Na+\<135milliequivalent per litre)

* Hypokalemia (K+ \< 5 milliequivalent per litre)

* Elevated liver enzymes

Critical - Severe features plus

* Anuria/ Acute renal failure

* Arrhythmia

* Pericardial effusion

* Massive hydrothorax

* Thrombo-embolism

* Arterial thrombosis

* (ARDS)Adult respiratory distress syndrome

* Sepsis - Worsening of biochemical

findings seen with severe OHSS

US: Ultrasound; Ht%:Ht; Hematocrit value; TLC: Total leucocytic count: ARDS; adult respiratory distress syndrome.

All patients are managed as outpatients unless management of severe symptoms necessitated hospital admission. Pain scores, serum E2 levels and MOD are evaluated daily. Patients are evaluated for associated symptoms previously determined during clinical evaluation, ascites grading and TLC and Ht value were evaluated at 3 and 6 days and on end of the trial on the 8th day after oocyte retrieval.

Recruitment & Eligibility

Status: UNKNOWN

Sex: Female

Target Recruitment: 48

Inclusion Criteria

number of retrieved oocytes was ≥20
mean number of follicles with a diameter of >16 mm was ≥18
serum E2 concentrations of ≥3500 pg/ml
ovarian diameter on the day of ovum retrieval of >10 cm
presentation of evident symptoms of OHSS on the day of aspiration .

Exclusion Criteria

1- Absence of one or more of the items of the inclusion criteria.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
cetrotide	Cetrorelix	study group (24 patients = intervention) received intervention for 3-daysCetrorelix Acetate sc injection (0.25 mg/day) started on Day-0. Serum E2, pain scores and MOD were checked daily. Hematocrit value (Ht%), total leucocytic count (TLC), gastrointestinal (GI) manifestations and ascites grading were re-evaluated on Day-3, 6 and 8.

Primary Outcome Measures

Name	Time	Method
Daily Serum E2 Levels	8 days	Serum E2 levels (Serum E2 level in picograms/ml) were evaluated daily.
Daily Maximal Ovarian Diameter	8 days	MOD (maximal ovarian diameter in mm) were evaluated daily.

Secondary Outcome Measures

Name	Time	Method
Ultrasound Detected Severity Grades of Ascites From Days 0-8	0-8 days	-US detected severity grades of ascites determined at Day -0, Day -3 and Day -8.
Daily Total Leucocytic Count	0 -8days.	TLC(x 1ooo cells/ml)
Daily Numerical Pain Visual Analogue Scale Score	8 days.	-All patients were clinically evaluated for the presence of abdominal pain and if present was graduated using a numerical pain visual analogue scale (VAS) with 0 means no pain and 10 means severe intolerable pain .
Daily Hematocrits Value	0-8 days.	Blood samples were obtained under complete aseptic condition for determination of hematocrits value (Ht%)