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Trial registered on ANZCTR


Registration number
ACTRN12613000017729
Ethics application status
Approved
Date submitted
14/12/2012
Date registered
8/01/2013
Date last updated
6/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Prophylactic pain medicine regimens for early medical abortion
Scientific title
Among women seeking medical abortion with misoprostol and mifepristone through 63 days' gestation with access to use of ibuprofen and codeine/paracetamol as needed, does prophylactic administration of tramadol 50 mg or ibuprofen 400 mg plus metoclopramide 10 mg administered immediately before misoprostol and then repeated four hours later decrease the maximal pain score reported at 8 hours following misoprostol use compared to women using placebos?
Secondary ID [1] 281693 0
None
Universal Trial Number (UTN)
U1111-1137-9139
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Medical Abortion 287966 0
Pain management 287967 0
Condition category
Condition code
Reproductive Health and Childbirth 288352 288352 0 0
Abortion
Anaesthesiology 288364 288364 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 1: Randomized to take tramadol 50 mg plus one placebo pill orally, immediately before taking the misoprostol dose (800 mcg vaginally or buccally), repeated once 4 hours later.

Group 2: Randomized to take ibuprofen 400 mg and metoclopramide 10 mg orally, immediately before taking the misoprostol dose (800 mcg vaginally or buccally), repeated once 4 hours later.

Group 3: Randomized to take two placebo pills orally, immediately before taking the misoprostol dose, repeated once 4 hours later.

All participants across treatment arms will also be given 4 tablets of ibuprofen 400 mg with instructions to take 1 tablet every 4 hours as needed, as well as 2 tablets of paracetamol with codeine with instructions to take 1 tablet every 4 hours as needed.

Medications will be pre-packaged with accompanying VAS forms to facilitate accurate diary assessments.
Intervention code [1] 286215 0
Prevention
Intervention code [2] 286230 0
Treatment: Drugs
Comparator / control treatment
Placebo tablets, immediately before taking the misoprostol dose, repeated once in 4 hours, followed by analgesics as needed for pain.

We anticipate encapsulating the study medicines/placebos to ensure adequate blinding of participants and study staff.
Control group
Placebo

Outcomes
Primary outcome [1] 288515 0
Compare the maximum pain level reported in the first 8 hours and first 24 hours after misoprostol administration across the three pain management strategies. To assess this outcome, all women will be instructed to record at 8 hours after misoprostol their maximum pain level as measured by VAS over the prior 8 hours in a symptom diary. All women will be instructed to record at 24 hours after misoprostol their maximum pain level as measured by VAS over the prior 24 hours in a symptom diary. These VAS scores in the treatment arms will be compared to the placebo arm and across groups.
Timepoint [1] 288515 0
At 8 hours and 24 hours
Secondary outcome [1] 300379 0
Compare the use of additional analgesics between the three pain management strategies. To address this outcome, we will compare the self recorded information pertaining to medication administration in the symptom diaries participants will complete. We will compare the use of additional analgesics across the randomized groups.
Timepoint [1] 300379 0
One week
Secondary outcome [2] 300380 0
Compare the use of additional narcotic analgesics between the three pain management strategies. To address this outcome, we will compare the self recorded information pertaining to medication administration in the symptom diaries participants will complete. We will compare the use of additional narcotics across the randomized groups.
Timepoint [2] 300380 0
One week
Secondary outcome [3] 300381 0
Determine if prophylactic use of the study medicines affects the effectiveness of the medical abortion regimen To assess this outcome, we will compare success rates of medical abortions as determined primarily by clinical history and exam confirmed by sonogram (when available).
Timepoint [3] 300381 0
One week
Secondary outcome [4] 300382 0
Evaluate the acceptability of the three pain management strategies and pain with the medical abortion process. To assess this outcome, we will perform 42 in-depth interviews with participants to learn more about their medical abortion experience, including their experience of pain and how it influenced their overall satisfaction with the method, and how they managed their pain. Fourteen women in each of the two study arms will be interviewed, evenly distributed among the study sites.
Timepoint [4] 300382 0
One month

Eligibility
Key inclusion criteria
Inclusion Criteria:

Woman seeking medical abortion with mifepristone and misoprostol up to 63 days' gestation as determined by the site

Age 18 or greater

Willingness to participate in randomized study
Ability to speak language(s) of site

Sufficient reading and writing literacy in the language of the site to be able to read study instructions and complete home self-assessments

Ability to give informed consent

Ability and willingness to be contacted by telephone
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for the study are:

Multiple gestation

Suspicion of any pathology of pregnancy (e.g. molar, ectopic, non-viable pregnancy, threatened abortion)

History of bleeding disorder or current anticoagulation therapy

Ongoing use (> 4 weeks) of metoclopramide prior to study initiation

Allergy to mifepristone or misoprostol

Allergy to tramadol, ibuprofen, metoclopramide, paracetamol or codeine

Gastritis or gastric ulcer or other contraindication to ibuprofen use

A history or evidence of disorders that represent a contraindication to the use of mifepristone or
misoprostol (chronic adrenal failure, severe asthma uncontrolled by corticosteroid therapy, inherited porphyries, glaucoma, mitral stenosis, hepatic or renal disease)


A history or evidence of disorders that represent a contraindication to the use of metoclopramide (pheochromocytoma, epilepsy, concurrent use of medications known to induce extrapyramidal symptoms)

A history or evidence of disorders that represent a contraindication to the use of tramadol (epilepsy, opioid dependency or alcohol abuse, concurrent use of medications known to result in CNS depression and/or lower seizure threshold)

Presence of an intrauterine contraceptive device

Severe anaemia (assessed clinically, or if measured, haemoglobin <9 mg/dl)

Inability to return to site for follow-up visit AND not accessible by telephone

No access to a time-keeping device

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be randomized to receive either tramadol 50 mg plus placebo, ibuprofen 400 mg plus metoclopramide 10 mg, or two placebo tablets to be taken immediately before the first misoprostol dose and repeated four hours later. They will be given 4 tablets of ibuprofen 400 mg with instructions to take 1 tablet every 4 hours as needed, as well as 2 tablets of paracetamol with codeine with instructions to take 1 tablet every 4 hours as needed. Medications will be pre-packaged with accompanying VAS forms to facilitate accurate diary assessments.

Women will be recruited from among those seeking medical abortion up to 63 days’ gestation at 3-4 study sites in different countries. Before initiating data collection at all sites, a pilot phase will be initiated at one site with an assessment of study feasibility after the first 30 participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
When the woman presents at the site requesting abortion, she will be evaluated in the standard manner at that site to determine if she is eligible for early medical abortion (EMA). If she is eligible for EMA, she will be given a brief description of the study and asked is if she is interested in participating. If she is interested, a screening case report form (CRF) will be used to determine if she is eligible for the study according to the inclusion and exclusion criteria.

If the woman meets the eligibility criteria, study staff will provide a copy of the consent form and read the form with the woman, answering any questions she might have. If the woman agrees to participate, she will be asked to sign the form. Consent for the abortion procedure will be obtained separate from the consent to participate in research.

Study staff will then collect the participant’s contact information, including the participant’s telephone number. A CRF will be completed with basic demographic information and clinical information (see below).

Women will be allocated to treatment by the study staff who will maintain a file of sequentially numbered, opaque, sealed envelopes containing the allocation. The randomization scheme will be created by an investigator not involved with the on-site study-related activities, and it will be based on computer-generated random permuted blocks (using STATA statistical software, version 10.0, College Station, TX). The allocation ratio will be one-to-one. Treatment allocation will be stratified according to parity (sample will be 50% nulliparous and 50% parous in each treatment arm) in order to avoid imbalances in parity between the two treatment groups.

Both women and study staff will be blinded with regard to their treatment. The placebo will appear similar to ibuprofen, and study drugs will be pre-packaged in the sealed envelopes.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Quantitative data: The primary outcome for this study will be the maximum recorded pain by VAS in the first 8 hours after misoprostol administration. Secondary outcomes include:
- maximum recorded pain by VAS in the first 24 hours after misoprostol
-use of any additional analgesic beyond study drug
-total number of pills taken (study drug/ placebo and any additional analgesics)

Categorical variables will be compared between the three treatment groups using chi-square tests; means will be compared using ANOVA. Logistic regression may be used to identify significant covariates that affect the outcomes.

All subjects will be included in the main analysis according to the intention-to-treat principle. However, subjects may be excluded from a secondary analysis (or analyzed separately) if one or more of the following apply:
-lack of essential data from the subject’s records making it impossible to judge treatment outcome;
-any violation of the study protocol including violation of eligibility criteria;
-treatment non-compliance.

Qualitative data: In-depth interviews will be audio recorded and transcribed verbatim, and we will code them using the qualitative software Atlas Ti; coding will be done of the interviewer’s notes if the participant did not consent to recording. Two investigators (or designees) will conduct a content analysis of the interview transcripts using the same software. The investigators (or designees) will independently read through the transcripts to identify common themes. The analysis will be an iterative process, whereby the investigators will be free to create and add new codes as the concepts emerge.

Sample size: 192 participants (96 nulliparous and 96 parous) will be randomly allocated to each of the three treatment arms. This sample size allows for 90% power to detect a difference of 1.5 in the reported maximal VAS pain measurement between arms while accounting for an anticipated 10% loss to follow up rate.

The sample size for this study is based on the primary outcome of maximum reported pain within 8 hours after taking misoprostol as measured by a visual analogue scale (VAS). VAS measurements for self-assessment of pain level have been extensively validated. Previous research found that the maximum VAS score with early medical abortion with mifepristone and misoprostol was 7, ranging from 5-8. Research has also reported that the minimally clinically significant difference in VAS scores is between 1.5 and 2. In order to detect a reduction in maximum VAS scores in the first 8 hours from 7 to 5.5, using a two-sided alpha of 0.05 and power of 90% while accounting for 10% loss to follow up, we will need 96 women in each study arm. There is an interest in determining the effect of prophylactic medication between both parity groups; thus, the sample size has been calculated to determine the effect of prophylactic medication among both parous and nulliparous women. Accounting for stratification by parity,we plan to enrol a total of 576 women. Because our treatment arms are independent of one another, we do not have to account for a multiplicity adjustment in our sample size calculations.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 4754 0
Nepal
State/province [1] 4754 0
Kathmandu
Country [2] 4755 0
South Africa
State/province [2] 4755 0
Rustenburg
Country [3] 4756 0
Viet Nam
State/province [3] 4756 0
Hanoi

Funding & Sponsors
Funding source category [1] 286470 0
Other
Name [1] 286470 0
World Health Organization
Department of Reproductive Health and Research
Address [1] 286470 0
Avenue Appia 20
1211 Geneve
Country [1] 286470 0
Switzerland
Primary sponsor type
Other
Name
World Health Organization
Address
Department of Reproductive Health and Research
Avenue Appia 20
1211 Geneve
Country
Switzerland
Secondary sponsor category [1] 285260 0
None
Name [1] 285260 0
Address [1] 285260 0
Country [1] 285260 0
Other collaborator category [1] 277224 0
Hospital
Name [1] 277224 0
Dr. Kusum Thapa
Department of Obstetrics and Gynecology, Paropkar Maternity and Women Hospital

Address [1] 277224 0
Thapathali, Kathmandu
Country [1] 277224 0
Nepal
Other collaborator category [2] 277225 0
Hospital
Name [2] 277225 0
Job Tabane Provincial Hospital
Address [2] 277225 0
Bosch St & Van Staden Street
Rustenburg, 0299
Country [2] 277225 0
South Africa
Other collaborator category [3] 277226 0
Hospital
Name [3] 277226 0
Dr. Duong Lan Dung
Department of Scientific Research, National Hospital of Obstetrics and Gynecology (NHOG)

Address [3] 277226 0
43 Trang Thi, Tran Hung Do, Hoan Kiem District
Hanoi


Country [3] 277226 0
Viet Nam

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288548 0
WHO Research Ethics Review Committee
Ethics committee address [1] 288548 0
Avenue Appia 20
1211 Geneve
Ethics committee country [1] 288548 0
Switzerland
Date submitted for ethics approval [1] 288548 0
Approval date [1] 288548 0
26/06/2014
Ethics approval number [1] 288548 0

Summary
Brief summary
Pain is a predictable feature of the medical abortion process, and for some women pain may be intense. Although pain is the most common side-effect encountered with medical abortion, little is known about optimal pain management during this process. Currently, WHO recommends use of NSAIDs during medical abortion with mifepristone and misoprostol. Previous studies have shown that NSAIDs, particularly ibuprofen, reduce pain once uterine cramping has started and is superior to paracetamol; however, it does not appear to be effective at preventing or minimizing the moderate to severe pain of medical abortion when administered alone prior to pain onset. As pain is often cited as one of the worst features of medical abortion, and given that inadequate pain management may motivate some women to seek unnecessary clinical care, there is a clear need to identify the most effective methods of pain control in this setting.

This study is a randomized, placebo-controlled trial of prophylactic analgesia for pain relief during early medical abortion with mifepristone and misoprostol. The primary objective of this study is to determine whether prophylactic administration of tramadol or ibuprofen plus metoclopramide is superior to analgesic administration after pain begins during the medical abortion process in terms of reducing maximal reported pain levels and subsequent use of pain medication (ibuprofen and oral narcotics).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 36638 0
Dr Daniel Grossman
Address 36638 0
Ibis Reproductive Health
1330 Broadway, Suite 1100
Oakland, CA 94612
Country 36638 0
United States of America
Phone 36638 0
1-510-986-8941
Fax 36638 0
1-510-986-8960
Email 36638 0
sanfran(at)ibisreproductivehealth.org
Contact person for public queries
Name 36639 0
Dr Daniel Grossman
Address 36639 0
1330 Broadway, Suite 1100
Oakland, CA 94612
Country 36639 0
United States of America
Phone 36639 0
1-510-986-8941
Fax 36639 0
1-510-986-8960
Email 36639 0
sanfran(at)ibisreproductivehealth.org
Contact person for scientific queries
Name 36640 0
Dr Daniel Grossman
Address 36640 0
1330 Broadway, Suite 1100
Oakland, CA 94612
Country 36640 0
United States of America
Phone 36640 0
1-510-986-8941
Fax 36640 0
1-510-986-8960
Email 36640 0
sanfran(at)ibisreproductivehealth.org

No information has been provided regarding IPD availability
Summary results
No Results