Study design and participants
The trial was a pragmatic, open-label, parallel arm randomised controlled trial conducted at two Eastern Cape hospitals, Frere Hospital (FH) and Cecelia Makiwane Hospital (CMH), in South Africa. Recruitment began on 6 July 2009 and ended on 8 November 2012. Women attending termination of pregnancy services at the study sites, who met the inclusion criteria and requested long-term contraception with no personal preference for a particular method, were counselled in their home language and offered participation in the trial. Women were eligible if they intended to continue contraception for at least one year, were ≥ 16 years old, had no evidence of active pelvic infection on history and clinical examination, had no contraindications to IPC or IUD use, were prepared to use either method of contraception, understood the patient information form, and were willing to sign informed consent. All women were offered counselling and voluntary HIV testing at baseline and at follow-up, according to national health policy, using rapid tests or laboratory-based ELISA tests. Those with positive results were offered a CD4 count and treatment according to national health guidelines.
Ethics, consent, and permissions
Ethical approval for the trial was obtained from the University of the Witwatersrand Committee for Research on Human Subjects, South Africa, on the 25 April 2008, clearance certificate M080466. Signed informed consent to participate in the study was obtained from all participants.
An allocation list was prepared using a computer-generated random sequence in balanced blocks of variable size and with a randomisation ratio of 1:1. Allocation slips were inserted into consecutively-numbered, opaque envelopes and sealed by a member of staff not involved in the trial. The randomisation list was sealed in a signed envelope by the same staff member for safekeeping. The randomisation envelopes were distributed to the study sites in batches of 100. Women who agreed to participate were entered onto a trial register and then enrolled by opening the next numbered, sealed envelope. The point of trial entry was at the opening of the envelope.
Women were fully counselled about their allocated contraception method prior to its administration. In the IUD group, the IUD was inserted after termination of pregnancy, which was usually performed by manual vacuum aspiration by the hospital staff following routine procedures. Antibiotic prophylaxis was not used. The women were offered two options regarding the string placement after full counselling about the relative benefits of each: strings protruding from the cervix by about 2 cm, or strings inserted completely within the uterine cavity or removed. The reason for offering these options is that many women in our services prefer their contraception to be confidential. In the IPC arm, women were counselled regarding the need for repeat injections at regular intervals. The first injection was administered by hospital staff according to routine practice and, in most instances, DMPA was used. However, as this was a pragmatic trial within the routine contraception services, allowance was made for the use of NET at the discretion of the provider. Women received no additional reminders to support continuation with the allocated contraception method, and no payments or other incentives were offered, other than payment of transport costs for the final visit at 12 months post-enrolment.
The primary outcome was pregnancy. Secondary outcomes were method discontinuation, side effects, HIV acquisition, and HIV/AIDS disease progression. Pregnancy and discontinuation outcomes are reported in this paper.
Professional nurses who worked as research assistants completed a Good Clinical Practice certification course before trial commencement. Participant baseline details were entered onto a paper case report form (CRF), including demographic data, medical history, and baseline data relevant to the follow-up questionnaire (including sexual activity and potential side effects). Follow-up questionnaires were administered by the research assistants to participants by telephone at three, six, nine and 12 months after randomisation. The CRF and questionnaire were piloted before the main trial. The actual contraceptive method received after randomisation was collected retrospectively from family planning registers at the two hospitals. Participants were requested to attend an interview at the hospital 12 months after enrolment, failing which the interview was conducted by telephone. Initial and final contraceptive methods used were confirmed with the participant at the last interview. Other questions at this interview included whether the participant had been pregnant since joining the study, the outcome of the pregnancy, and what contraceptive methods had been used since joining the study, as well as reasons for discontinuation. Attempts to contact women who did not return for follow-up were continued until study closure in June 2014. Research assistants advised participants to attend the relevant health facility for any health concerns.
Sample size and analysis
The sample size was calculated based on the primary outcome. To detect a reduction in unplanned pregnancy from 2.5 % to 1.5 %, we calculated that we needed 6,546 participants (alpha = 0.05, beta = 0.20; Epi Info™ statistical software version 7). To allow for loss to follow-up, we planned to recruit a total sample size of 7,000 women.
Intention-to-treat analysis was performed for the primary outcome (pregnancy) using Epi Info™ statistical software. Discontinuation rate was defined as the proportion of women who did not continue use of the allocated method to follow-up, out of the women initiating the allocated method and this analysis was, thus, per protocol.
Baseline characteristics were compared between enrolled groups, as well as those with follow up of 12 months or more. For categorical variables, the rates of outcome events were compared as risk ratios (RR) with 95 % confidence intervals (CI). P-values were calculated using the Chi-squared test with Mantel-Haenszel correction or, for small numbers, the Fisher’s exact test. P values of less than 0.05 were regarded as statistically significant.
Registration of the protocol with the South African National Clinical Trials Register was undertaken on 15 September 2008 (Verification Code: 0–953). It was subsequently found not to have been logged by the system, and was re-registered with the Pan African Clinical Trials Registry on 4th September 2014 (PACTR201409000880157). (http://apps.who.int/trialsearch/Trial2.aspx?TrialID=PACTR201409000880157).