A Non-inferiority Trial on Pain Relief During Oocyte Retrieval

• Sponsor: Kwong Wah Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02494180
• Collaborator: The University of Hong Kong (Other), Queen Mary Hospital, Hong Kong (Other)
• Enrollment: 170
• Arms: 2
• Actual Duration (Months): 23.1

Study Details

Study Description

Brief Summary

The objective of the trial is to compare fentanyl and midazolam vs diazepam and pethidine in terms of the pain levels and post-operative side effects of TUGOR

Condition or Disease	Intervention/Treatment	Phase
Infertility	Drug: fentanyl; Drug: pethidine; Drug: Diazepam; Drug: Midazolam	Phase 4

Detailed Description

In-vitro fertilization / embryo transfer (IVF / ET) is a well-established method to treat various causes of infertility. It involves multiple follicular development, retrieval of oocytes and embryo transfer after fertilization. Egg retrieval at the majority of IVF units is performed through the transvaginal route under ultrasound guidance (TUGOR) [1]. During TUGOR, the needle has to pass through the mucosa in the vaginal vault in order to puncture the follicles in the ovary. The procedures are generally short, lasting about 20-30 minutes but are still painful without anaesthesia or analgesia.

Intravenous sedation with or without local anaesthesia is the most widely used method. Conscious sedation is a safe and cost-effective method of providing analgesia and anesthesia for TUGOR. [2] It is easy to administer in cooperative and motivated patients. It has a relatively low risk for adverse effects on oocyte and embryo quality and pregnancy rates. [3] Paracervical block (PCB) in conjunction with conscious sedation during TUGOR was shown to significantly reduce the pain during TUGOR when compared to PCB alone [4].

A Cochrane review on various methods of sedation and analgesia for pain relief during TUGOR has shown no single method or delivery system appeared superior for pregnancy rates and pain relief. [5] Most of the methods seemed to work well and the effect was usually enhanced by addition of another method such as pain relief with paracervical block. [6]

The investigators' reproductive centre has recently aligned with the Assisted Reproduction Centre of the University of Hong Kong (HKU). The investigators are using 0.1mg fentanyl and 5mg midazolam intravenously for pain relief in TUGOR at Kwong Wah Hospital (KWH) whereas 5mg diazepam and 25mg pethidine intravenously are being used in HKU. The investigators would like to compare fentanyl and midazolam vs diazepam and pethidine in terms of pain levels and post-operative side effects of TUGOR in this prospective non-inferiority randomized double-blinded trial. The investigators postulate there are no differences in the pain levels between two groups but the postoperative side effects may be different.

Study Design

• Study Type: Interventional
• Actual Enrollment: 170 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Supportive Care
• Official Title: A Prospective, Non-inferiority Randomized Double-blinded Trial Comparing Fentanyl and Midazolam vs Diazepam and Pethidine for Pain Relief During Oocyte Retrieval
• Actual Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Feb 1, 2018
• Actual Study Completion Date: Feb 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: A: intravenous fentanyl, midazolam group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval	Drug: fentanyl; arm A receiving iv fentanyl; Drug: Midazolam; arm A receiving iv midazolam; Other Names: dormicum
Placebo Comparator: B: intravenous pethidine, diazepam group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval	Drug: pethidine; arm B receiving iv pethidine; Drug: Diazepam; arm B receiving iv diazepam; Other Names: valium

Outcome Measures

Primary Outcome Measures

1. Pain Level During Oocyte Retrieval [will be assessed within 4 hours of oocyte retrieval]

   The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful

2. Pain Level After Oocyte Retrieval [will be assessed within 4 hours of oocyte retrieval]

   The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful

Secondary Outcome Measures

1. Percentage of Participants With Side Effects by Type [will be assessed within 4 hours of oocyte retrieval]

   side effects will be scored by yes or no

2. Patient's Satisfaction on Oocyte Retrieval [will be assessed within 4 hours of oocyte retrieval]

   satisfaction will be scored from 0-3 (0=excellent, 1=satisfactory, 2=fair, 3=unsatisfactory)

3. Clinical Pregnancy Rate [will be assessed within ten weeks of oocyte retrieval]

   presence of intrauterine sac in ultrasound after a positive pregnancy test

4. Ongoing Pregnancy Rate [will be assessed within ten weeks of oocyte retrieval]

   positive fetal heart pulsation seen in ultrasound at eight weeks of gestation

5. Patient's Satisfaction on Pain Relief [within 4 hours after retrieval]

   satisfaction on pain relief will be scored at 0-10 (10 being most satisfied)

6. Sedation Level [immediately after retrieval]

   S = sleeping, easily aroused; 1 = awake and alert; 2 = occasionally drowsy, easy to arouse; 3 = frequently drowsy, arousable, drifts off to sleep during conversation; 4 = somnolent, minimal or no response to stimuli

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• presence of both ovaries;

• body mass index less than 30

• written informed consent and

• Chinese

Exclusion Criteria:

• IVF cycle converted from ovulation induction or intrauterine insemination cycles;

• patient requests general anaesthesia for TUGOR;

• history of drug sensitivity to lignocaine/fentanyl/midazolam/diazepam/pethidine;

• less than 3 dominant follicles present;

• dominant follicles present in one ovary only and

• TUGOR performed on one side only.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Kwong Wah Hospital
• The University of Hong Kong
• Queen Mary Hospital, Hong Kong

Investigators

• Principal Investigator: Shui Fan Lai, Kwong Wah Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 24, 2015

More Information

Publications

None provided.

• Responsible Party: lydia lai, Associate Consultant, Kwong Wah Hospital
• ClinicalTrials.gov Identifier: NCT02494180
• Other Study ID Numbers: KW/FR-15-021(83-22)
• First Posted: Jul 10, 2015
• Last Update Posted: Mar 5, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by lydia lai, Associate Consultant, Kwong Wah Hospital: fentanyl; midazolam; pethidine; diazepam
• Additional relevant MeSH terms: Infertility; Fentanyl; Midazolam; Diazepam; Meperidine

Study Results

Participant Flow

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Period Title: Overall Study
STARTED	85	85
COMPLETED	85	85
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam	Total
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam	Total of all reporting groups
Overall Participants	85	85	170
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	36	37	37
Sex: Female, Male (Count of Participants)
Female	85 100%	85 100%	170 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	85 100%	85 100%	170 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Hong Kong	85 100%	85 100%	170 100%

Outcome Measures

1. Primary Outcome

Title	Pain Level During Oocyte Retrieval
Description	The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful
Time Frame	will be assessed within 4 hours of oocyte retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
vaginal pain	0	4
abdominal pain	2.5	5

2. Primary Outcome

Title	Pain Level After Oocyte Retrieval
Description	The pain level will be scored using visual analogue scale 0-10, 0 = no pain, 10 =most painful
Time Frame	will be assessed within 4 hours of oocyte retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
vaginal pain	0	0
abdominal pain	2.3	2

3. Secondary Outcome

Title	Percentage of Participants With Side Effects by Type
Description	side effects will be scored by yes or no
Time Frame	will be assessed within 4 hours of oocyte retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
nausea	2.4 2.8%	7.1 8.4%
vomiting	0 0%	1.2 1.4%
dizziness	16.5 19.4%	4.7 5.5%
drowsiness	8.2 9.6%	3.5 4.1%
shortness of breath	0 0%	1.2 1.4%

4. Secondary Outcome

Title	Patient's Satisfaction on Oocyte Retrieval
Description	satisfaction will be scored from 0-3 (0=excellent, 1=satisfactory, 2=fair, 3=unsatisfactory)
Time Frame	will be assessed within 4 hours of oocyte retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
excellent	47.7 56.1%	15.3 18%
satisfactory	38.8 45.6%	55.3 65.1%
fair	11.8 13.9%	22.4 26.4%
unsatisfactory	4.7 5.5%	7.1 8.4%

5. Secondary Outcome

Title	Clinical Pregnancy Rate
Description	presence of intrauterine sac in ultrasound after a positive pregnancy test
Time Frame	will be assessed within ten weeks of oocyte retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
Number [percentage of participants]	14.1 16.6%	23.5 27.6%

6. Secondary Outcome

Title	Ongoing Pregnancy Rate
Description	positive fetal heart pulsation seen in ultrasound at eight weeks of gestation
Time Frame	will be assessed within ten weeks of oocyte retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
Number [percentage of participants]	12.9 15.2%	21.2 24.9%

7. Secondary Outcome

Title	Patient's Satisfaction on Pain Relief
Description	satisfaction on pain relief will be scored at 0-10 (10 being most satisfied)
Time Frame	within 4 hours after retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
Median (Inter-Quartile Range) [score on a scale]	8	7

8. Secondary Outcome

Title	Sedation Level
Description	S = sleeping, easily aroused; 1 = awake and alert; 2 = occasionally drowsy, easy to arouse; 3 = frequently drowsy, arousable, drifts off to sleep during conversation; 4 = somnolent, minimal or no response to stimuli
Time Frame	immediately after retrieval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Intravenous Fentanyl, Midazolam	B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam	group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
Measure Participants	85	85
1	15 17.6%	52 61.2%
2	14 16.5%	17 20%
3	16 18.8%	4 4.7%
4	21 24.7%	5 5.9%
S	18 21.2%	7 8.2%
missing data	1 1.2%	0 0%

Adverse Events

Time Frame	within 18 days of hCG which is also the urine pregnancy test date
Arm/Group Title	A: Intravenous Fentanyl, Midazolam		B: Intravenous Pethidine, Diazepam
Arm/Group Description	group A will be given intravenous 0.1mg fentanyl and 5mg midazolam prior oocyte retrieval fentanyl: arm A receiving iv fentanyl Midazolam: arm A receiving iv midazolam		group B will be given intravenous 25mg pethidine, 5mg diazepam prior oocyte retrieval pethidine: arm B receiving iv pethidine Diazepam: arm B receiving iv diazepam
All Cause Mortality
	A: Intravenous Fentanyl, Midazolam		B: Intravenous Pethidine, Diazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		0/85 (0%)
Serious Adverse Events
	A: Intravenous Fentanyl, Midazolam		B: Intravenous Pethidine, Diazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		0/85 (0%)
Other (Not Including Serious) Adverse Events
	A: Intravenous Fentanyl, Midazolam		B: Intravenous Pethidine, Diazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		0/85 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.