2.1. Contrato de préstamo de mutuo
2.1.9 Jurisprudencia
Both a general and central nervous system (CNS) examination, and functional
neurodevelopmental assessment (NDA) were carried out on the first visit following a standard protocol (Section 6.6.1, point B). The psychological and behavioural assessment tools used are described in Section 4.7, and 4.8. A second behavioural assessment was conducted after 12 months of regular treatment or at the time of drug withdrawal. Our behavioural assessment instruments were adapted and validated in the same region using the local language (Section 4.8 and 4.9)
7.2.7: Seizure outcome
Seizure outcome was recorded as percentage of seizure reduction and then categorized as ‘seizure remission’ or ‘no seizure remission’ (Point 18 in Section 4.3.1).
7.2.8: Simple randomization
Fifty-four papers with drug A (phenobarbitone), and other 54 papers with drug B (carbamazepine) written on them were folded twice and sealed each in an envelope. The 108 sealed envelopes were shuffled and then kept under lock and key by the researcher. Once the child had fulfilled the RCT enrolment criteria consent was obtained from the parent, and an envelope was picked up by a reliable person who did not have any part in the research work.
For practical and ethical reasons the treating physician was aware o f the treatment drug. Other research assistants, i.e., the psychologist, therapist and the researcher were blind to the treatment. The researcher was only made aware during the data analysis. Drugs were supplied by the clinic. We developed methods o f ensuring the medicine supply if the family failed to attend clinic or temporarily moved. Depending on the family needs and distance from the clinic, either sufficient numbers o f tablets were supplied or any of the family members were able to collect the medicine, or parents
would buy the medicine from the nearest pharmacy, then the clinic would refund on presentation o f receipts and tablet strips.
Compliance was ensured by verbal reply and by counting the remaining tablets. Blood tests for detection of drug levels were carried out on one occasion without a previous warning to the parents.
Participants were supplied with a hand-made seizure diary (Appendix XVI), in which they were trained to record the events by putting a mark or a dot for a major or a minor attack.
Patients were reviewed at two weeks, one month, three month, or six-month intervals depending on the therapeutic response and distance o f the family residence. During each visit the physician recorded their immediate complaints and the number of seizure attacks or rate of seizures since the last visit. The AED dose was calculated and
adjusted with the rate of seizure control and recent body weight o f the child. The list of side-effects was checked at each visit.
7.2.9: Drugs and doses
Phenobarbitone was available as 30mg tablets in strips, and carbamazepine as 200mg in strips. Treatment was started with a low, weight-related dose and was increased after 2 weeks following the WHO recommendation (Gastaut & Osontokun 1976a). Phenobarbitone was started at 1.5 mg/kg/day taken in two divided doses and the maintenance dose was 3 mg/kg. Carbamazepine was started at 5mg/kg daily and increased to 10 mg/kg in 2 weeks then 16 mg/kg after another 2 weeks as a
maintenance dose. A maximum of 4 mg/kg per day for phenobarbitone and 20 mg/kg per day for carbamazepine was allowed until effective seizures control was achieved. If seizures were not controlled, despite the full dose and blood level results being within a therapeutic level, treatment was changed to the other study drug while the previous one was weaned. If seizure control was achieved while weaning the previous drug and increasing the new drug the combination was maintained (WHO & anther’s previous experience). If none of the trial drugs were effective or there was complaint
o f unacceptable side effect from both the trial drugs a third suitable AED was introduced. However, when a patient had to change the randomised drug s/he was withdrawn from the trial and recorded as ‘drug failed’.
All participants were followed up for a minimum o f 12 months after randomization.
7.2.10: Outcome measures
The main outcome measure was behavioural side effects recorded as either complaints from the parents (check list. Appendix III) o f hyperactivity, irritability and
aggressiveness or a behavioural assessment score compared with the score before starting treatment. Formal behavioural assessment scores were reported as continuous variables.
Parental impressions of any change o f their children’s behaviour after starting the AED treatment were categorized as ‘deteriorated’, ‘unchanged’ or ‘improved’ compared to before treatment To assess the drug efficacy, the following data were collected: (1) date of treatment allocation; (2) time to first seizure post randomisation; (3) time to treatment withdrawal due to adverse effects and (4) date of last follow-up.
7.2.11: Analysis
The analysis was based on the policy of intention to treat. The primary aim of the analysis was to compare the drug side effects. Parametric, independent sample Mests and nonparametric, Mann Whitney tests were used to measure the difference of behavioural side effects. Paired sample r-tests were done to compare the difference of behavioural assessment scores before and after treatment within the trial groups. The drug efficacy was compared using the time to first seizure after randomization as the primary data. The Kaplan-Meier test was applied to the time from randomization to first date of seizure or to the date of last follow-up when there was no recorded seizure after randomization. Behaviour outcome were analysed, both unadjusted and adjusted for motor disorder and cognitive impairment. The Cox-regression test was performed to analyse correlation of age, sex, presence or absence o f motor disability and cognitive impairment with the outcome behavioural problem.
F igure-7.1 Trial profile:
42 continued PB 45 continued CBZ
54 assigned phénobarbital 54 assigned carbamazepine 108 eligible for RCT
423 children recruited with seizure disorders
Followed up 12 months 42 for seizure outcome 40 for behavioural outcome
Followed up 12 months 49 for seizure outcome 45 for behavioural outcome
14 withdravm 12 lost to follow up 2 changed trial drug for poor seizure control.
9 withdrawn 5 lost to follow up 4 changed trial drug for poor seizure control
7.3: Results
O f the 108 patients eligible for the drug trial, 91 (84.3%) children were followed up and continued the regular treatment. Sixty-one (67.0%) children came to the clinic regularly, 30 (33%) needed recall by letter, telephone and/or home visit before the final follow-up at one year. Seventeen patients (15.7%) were untraced.
O f the 91 children, 6 had to change drugs due to poor seizure control or the occurrence of other seizure types for example, myoclonic seizures. Eighty-five children (40 in PB & 45 in CBZ group) continued with the drug trial for 12 months.
The family characteristics are shown in Table 7.1. The majority o f children came from poor and middle class families in rural area. Most of the families travelled from rural residences, and sometimes from remote countryside by foot, bus, boat or train,
involving great effort and often hardship. Minimum and maximum transportation cost for each visit were taka 20 and taka 5000. Maternal illiteracy was recorded in 40% of the families.