Modificación de los Artículos 240 y 243, 244 de Ley N° 27287, Ley de Títulos Valores

The trial was co-ordinated from a central trial office located within the University of Nottingham, with the day-to-day running supervised and organised by a local trial management group and trial manager. The trial was sponsored by the University of Nottingham and conducted in accordance with good clinical practice (GCP) guidelines. All research staff received GCP and research governance training in addition to the study-specific training. Monthly research staff meetings were held in Nottingham, which all RMs were encouraged to attend; the aim was to keep them motivated, updated and trained, as well as to give them the opportunity to network with each other.

In addition to GCP and research governance training, all RMs were trained to English national standards in delivering smoking cessation advice, with particular emphasis on the issues faced by pregnant smokers. RMs completed the 2-day training before they started recruiting, with additional refresher training during the trial. The general aim of training was to provide RMs with an understanding of the basic epidemiology of smoking behaviour, the motivations behind this, harm caused by smoking and environmental tobacco smoke exposure, why people smoke and key barriers to quitting experienced by those smokers who attempt cessation. Skills-focused sessions also aimed to equip RMs with the counselling skills required to help smokers to begin thinking differently about their habit (cognitive change) and to apply recognised techniques to overcoming their addiction (behavioural change). RMs were trained to put emphasis on the value of behavioural approaches for cessation in pregnancy, on the uncertainty regarding the efficacy of NRT and the inappropriateness of using either bupropion or varenicline in pregnancy. In addition, they were trained to counsel participants in the appropriate use of patches (i.e. as if all were issued with active patches) and to instruct them not to smoke or use non-trial NRT preparations in addition to trial medications.

The NCTU provided a web-based database and randomisation system, data management reports and MedDRA coding of AEs. The system was held on a secure server in the NCTU, had a full electronic audit trail and full back-ups of the database were made every 24 hours. Baseline and follow-up data were collected on paper case report forms (CRFs) or questionnaires and then inputted onto the database by the RM or trial administrator. The database included validation checks on data fields, whereby responses not meeting expected criteria would be flagged so that data entry errors were minimised. The trial

administrator or trial manager checked all database entries contributing to the outcomes at delivery against the CRF and clarified any queries with RMs. In addition, 10% of follow-up questionnaires were checked against database entries.

The independent TSC and the DMC met once or twice per year to monitor and supervise the progress and conduct of the trial and to review any safety or data issues. The DMC received blinded outcome data each time it met. Stopping rules were established such that if quit rates in the whole sample fell below 4%, or if recruitment rates fell below 25% of the target, then they would consider recommending that the trial be stopped.

Oxfordshire Research Committee A granted national research ethical approval, with additional local approvals for each recruitment centre and Clinical Trial Authorisation (CTA) approval from the MHRA (CTA number: 03057/0002/001-0001). The protocol was published,55_{with several approved amendments made}

to the original protocol after the start of recruitment; details of these amendments are given below (see

Protocol amendments) and the final protocol can be found inAppendix 3. The trial was registered on the ISRCRN database (ISRCTN07249128) and was assigned a EudraCT number (2004-002621-46). The NHS National Institute for Health Research (NIHR) Primary Care Research Network adopted the study.

Bulk supplies of the NRT and placebo patches were manufactured by United Pharmaceuticals, purchased at market rates and imported into the EU via Almac Ltd, Clinical Trial Services, Craigavon, Northern Ireland. QMC Clinical Trials Pharmacy at Nottingham University Hospitals NHS Trust managed quality control testing, packaging and labelling of participant packs. To ensure stability for the whole study period, the

patches needed to be stored refrigerated at 2–8 °C before being dispensed to participants. However, as the drug was stable at temperatures of<25 °C for 3 months, and only 1 month’s supply of patches was issued at a time, it was not necessary for participants to store them in a refrigerator.

Baseline and 1-month saliva samples were analysed at laboratories within the Centre for Oncology and Molecular Medicine, Division of Medical Sciences at the University of Dundee, UK, under the overall supervision of Professor Michael Coughtrie (a co-investigator). Baseline blood samples were analysed by ABS Laboratories Ltd, Welwyn Garden City, Hertfordshire, UK, and saliva samples taken at delivery were analysed by Salimetrics Europe Ltd, Newmarket, Suffolk, UK.

Protocol amendments

Brief details of protocol amendments made after the start of recruitment, but prior to breaking treatment allocation codes, are listed below.

1. We originally anticipated that women would be sent the PIS before their clinic appointments so that they could then be recruited and consented when they attended for their antenatal scan appointment. However, it was soon realised that, overall, this was not a practical option and that most women were being enrolled on home visits. Therefore, rather than posting the PIS to all women, we added the option of just sending leaflets containing brief information about the trial, with the full PIS later posted to women who had been identified and contacted using the screening questionnaire.

2. Small changes were made to the protocol to clarify trial processes and allow for minor variations in practice in the different centres due to different local arrangements in, for example, prescribing and dispensing practices, local clinic arrangements, follow-up cessation support and time spent in hospital after delivery.

3. Ambiguities in the primary outcome measure were addressed and clarified in the protocol, including the time window in which data collected could be used for analysis, how self-report and biochemical validation data of smoking cessation contributed to a positive primary outcome and what constitutes

‘prolonged abstinence from smoking’. Secondary outcomes were clarified to distinguish and define fetal death at different gestations, i.e. miscarriage and stillbirth.

4. We obtained ethical approval to send a‘congratulations on the birth of your baby’card to women after delivery.

5. The content of the questionnaires sent at 6 months, 1 year and 2 years after delivery was finalised and approved, along with a questionnaire to be sent to participants when they could not be contacted 1 month after their quit date. We also decided to include incentives of shopping vouchers and a colouring competition to help improve response rates for the 2-year questionnaires.41

6. Once the trial started, we realised that as many pregnancy-related conditions required hospital

admissions this was resulting in a large number of SAE reports, none of which were felt to be related to the study drug. Therefore, the sponsor and TSC recommended that we should extend the list of

conditions in the protocol that did not need to be reported as a SAE (any deaths of the mother or fetus/ infant were still reported). All these AEs were still collected and reviewed by the DMC so that

unforeseen impacts of NRT could be monitored.

7. Following further stability data from the manufacturer of the nicotine and placebo patches used in the study, the shelf life was extended from 24 to 42 months.

Trial extensions

The HTA granted two time extensions to the application, adding a total of 12 months to the original length of the trial. This was necessary as the start of recruitment was slightly delayed and the overall recruitment period took 10 months longer than the original estimate of 24 months. Careful budgeting of trial resources funded the majority of this extension, but a small addition to the budget was also awarded.

Chapter 3

Results