Study design and treatments
This was a single-centre, prospective, two-sequence, two-period
crossover study, in which healthy male subjects were randomised to
receive 400 mg zamicastat or placebo.
The study had a double-blind design and was placebo controlled to
reduced potential bias. Compared with a parallel-group study, the
crossover design reduces the influence of confounding covariates and
provides more precise estimates of effects with fewer participants.
The study consisted of a screening evaluation, two treatment periods,
and an end-of-study visit. In each treatment period, subjects were
administered a 400 mg once-daily oral dose of zamicastat or matching
placebo, for 10 days, in fed conditions. The two treatment periods were
separated by a washout of at least seven days. Subjects were screened
between days -28 to -3 (both inclusive) before the first IMP
administration to confirm that they met the eligibility criteria for the
study (Figure 1).
On both treatment periods, subjects were admitted to the clinical site
two days before (day -2) the first IMP administration. On both treatment
periods, the following procedures were completed on the day before (day
-1) the first IMP administration: measurement of vital signs (BP, HR,
and body temperature); 24-hour urine collection for catecholamines
assay; collection of blood for plasma catecholamines concentration, DβH
activity determination, and zamicastat and metabolites (BIA 5-453 and
BIA 5-961) quantification; and CPT.
On the morning of days 1 to 10, subjects received 400 mg of zamicastat
or matching placebo orally, after a moderate breakfast. On days 3, 6, 8,
and 10, 24-hour urine was collected for catecholamines assay, and blood
samples were collected for DβH activity determination and zamicastat and
metabolites quantification. On day 1 and day 10, CPT was performed, and
blood was collected for the determination of plasma catecholamines
concentration, before and after CPT.
During the treatment days, the following safety assessments were
performed: clinical laboratory safety test on day 5 (haematology and
biochemistry); ECG on days 1, 3, 5, 7, and 9; and vital signs from day 1
to 10.