Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple. PubMed was searched to identify publications about the characteristics of different trial designs that can be used in randomised, comparative small clinical trials. In addition, the contents tables from 11 journals were hand-searched. An algorithm was developed using decision nodes based on the characteristics of the identified trial designs. We identified 75 publications that reported the characteristics of 12 randomised, comparative trial designs that can be used in for the evaluation of therapies in orphan diseases. The main characteristics and the advantages and limitations of these designs were summarised and used to develop an algorithm that may be used to help select an appropriate design for a given clinical situation. We used examples from publications of given disease-treatment-outcome situations, in which the investigators had used a particular trial design, to illustrate the use of the algorithm for the identification of possible alternative designs. The algorithm that we propose could be a useful tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation.
Summary— Twenty‐four infants, 1 to 18 months‐old, who were referred to four centers for suspected gastroesophageal reflux and whose esophageal pH after a standard formula meal given at 9 to 10 am (Ho‐day 1) fulfilled the criterion of being < 4 for more than 5% of the time between H 1 and H 6 , entered a double‐blind placebo‐controlled dose‐response trial of metoclopramide (M). Twenty‐four hours later (day 2), patients were randomly assigned to receive either placebo or a single 0.1, 0.2, or 0.4 mg/kg dose of metoclopramide, 30 min before the formula meal ( n = 6/group) and the procedure was repeated. Metoclopramide plasma concentration was measured 1 h after dosing (C 1h ). On day 1, the time during which the esophageal pH was < 4 (time pH < 4), and five other parameters, were not significantly different in the treatment groups. On day 2, time pH < 4 (m(SD)) decreased from 33(13) to 30(33), 39(27), to 36(47), 42(15) to 18(13) and 48(25) to 31(46) min in the placebo, 0.1, 0.2, and 0.4 mg/kg metoclopramide groups, respectively. Possibly due to the large interindividual variability, no significant differences in parameters were observed between the different groups. None of the parameters correlated with the metoclopramide dose. Time pH < 4 expressed as the difference between day 1 and day 2, relative to day 1, decreased significantly as a function of C 1h . No side effects were observed. A similar study should be performed after repeated dosing regimen.
Isoniazid acetylation metabolic ratio (MR) was studied in 61 children with tuberculosis after administration of isoniazid. MR was calculated as the molar acetylisoniazid to isoniazid concentration ratio. MR was used as a probe for N-acetyltransferase activity and to determine the acetylation phenotype. MR had a bimodal distribution with an antimode between 0.48 and 0.77. MR and the percentage of fast acetylators increased significantly with age. The cumulative frequency of fast acetylators increased with age, with a plateau reached around 4 years. MR value was checked during treatment in 44 children. All children but one who initially appeared as fast acetylators remained in this group after repeated testing. Among the 30 slow acetylators, 12 became fast acetylators, and 10 showed a variable phenotyping at different ages. A bimodal distribution of the isoniazid acetylation MR was shown in children, with an antimode close to that described in the literature and a maturation of isoniazid acetylation during the first 4 years. Clinical Pharmacology & Therapeutics (1997) 62, 377–383; doi:
Eight children (3.84 +/- 1.17 years old) received a single oral 5 mg cetirizine dose (0.32 +/- 0.07 mg.kg-1) as a 10 mg.ml-1 solution, 1.73 (+/- 0.64) hours before a minor surgical intervention (mean duration +/- SD = 0.90 +/- 0.25 h). Seven venous blood samples were collected before administration (t0) and 0.5 h, 1.5 h, 4 h, 8 h, 12 h and 24 h after dosing, and urine samples were collected up to 24 hours after the dose. The mean +/- SD kinetic parameters were: peak plasma level (Cmax) 607 +/- 231 micrograms.l-1 reached in 1.93 +/- 1.39 h (tmax), elimination half-life (t1/2) 5.55 +/- 0.98 h, area under the plasma concentration time curve (AUC0-infinity) 4,772.1 +/- 1,318.4 micrograms.l-1.h, mean residence time (MRT) 8.13 +/- 1.31 h, apparent plasma clearance (Cl/f) 1.27 +/- 0.80 ml.min-1.kg-1, apparent volume of distribution (Vz/f) 0.60 +/- 0.38 l.kg-1. Urinary recovery was 38.4 +/- 9.9% (n = 4) of the dose. Renal clearance was 0.42 +/- 0.10 ml.min-1.kg-1 (n = 6). No influence of age on the cetirizine parameters was evidenced among this group, except for MRT (p < 0.05) which decreases with age. When compared with results in adults, elimination half-life (t1/2) was twice as short and apparent clearance twice as great. These results suggest that a higher dosage b.i.d. may be required in children.
This two-part, open-label study evaluated the pharmacokinetics, safety, and tolerability of oxcarbazepine as combination therapy in 112 children 2 to 12 years old with inadequately controlled epilepsy. Part I was a pharmacokinetic study in children stratified by age (2-5 years and 6-12 years) and randomized to receive a single oxcarbazepine dose of 5 mg/kg or 15 mg/kg. Mean specific AUC and t(1/2) values of the active metabolite (MHD) were approximately 30% lower in younger children compared with older children, regardless of dose. Part II was a 4-month safety, tolerability, and pharmacokinetic study in which children received oxcarbazepine doses of 11 to 68 mg/kg/day. The mean specific oxcarbazepine daily dose was 38% higher in younger children compared with older children. Similarly, mean trough plasma MHD concentrations were 34% lower in younger children. Six (5%) children discontinued due to adverse events. Oxcarbazepine was safe and well tolerated. Younger children require higher oxcarbazepine doses because of rapid clearance.
