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Source: Summarized from Temple (1982).

Source: Summarized from Temple (1982).

baseline between captopril and placebo, reaches a plateau and remain constant after dosing period 2 during which 50 mg t.i.d. was administered. Consequently, Temple (1982) suggests that 50 mg t.i.d. seems to treat most hypertensive patients well.

Forced Dose-Escalation Design

The design illustrated in Table 5.5.2 is an example of the optional titration design mentioned above. Inclusion of a parallel concurrent placebo control group can correct for spontaneous changes and investigator expectations. As each subject in titration designs receives several different doses, in addition to population average dose-response relationship, individual dose-response information can be obtained. In addition, with a careful planning, the titration design may require fewer subjects than the fixed-dose parallel dose response design and fewer subjects may be exposed to higher doses. However, time and dose are confounded with each other. This problem will become particularly troublesome when one tries to characterize the dose-response relationship for adverse events.

Note that some pharmaceutical agents might induce some undesirable but reversible safety concerns. In addition they may not be efficacious at lower doses. When conducting clinical trials with these agents, we would expect a significant number of dropouts. Therefore it is recommended that a trial with these agents begin very cautiously with a very low dose. In such a trial the criteria for titration process is based on safety rather than efficacy because the drug is unlikely to be effective at lower doses. As a result all patients who do not have the predefined safety problem will be forced to receive the next higher dose in the subsequent dosing period. This type of titration design is called the forced dose-escalation design. A typical example for obtaining FDA approval using the forced dose-escalation trials is the approval of Tacrine which is intended for treatment of mild to moderate dementia of the Alzheimer's type. Since Tacrine is known to induce elevation of serum alanine aminotrans-ferase (ALT) above the upper limit of the normal range in 43% to 54% of the patients and around 28% of the patients treated with Tacrine showed an elevation of ALT exceeding three times the upper limit of the normal range, the forced dose-escalation design at six-week intervals was chosen for two adequate well-controlled studies for the approval of the drug. The design of the first adequate well-controlled randomized study is a 12-week trial that consists of two six-week double-blind phases with the placebo current control groups as shown in Table 5.5.3 (Farlow et al., 1992). Patients were first randomized to one of the six sequences. For the double-blind phase I the patients in sequences 1 and 2, 3 and 4, and 5 and 6 received placebo, 20 mg, and 40 mg per day, respectively. However, for the double-blind phase II

Table 5.5.3 Forced Dose-Escalation Design for 12-Week Trial of Tacrine in Alzheimer's Disease

Randomized Sequences

Double-Blind Phase I Week 1 to 6

Double-Blind Phase II Week 7 to 12

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