ence (alpha = 0.025, single tail) in the attack rate for clinical malaria in vaccinees versus controls (based on estimated 60 percent vaccine efficacy and a lower limit of 30 percent for the 95 percent confidence interval [CI]), the trial would have to be large enough to allow detection of a total of 160 confirmed P. falciparum clinical malaria cases.
Some assumptions for design of the trials without chemoprophylaxis include the following:
At least 70 percent of the U.S. control subjects will develop clinical malaria during approximately 5 months of stay in peak transmission season. (It is recognized that this is likely a conservative estimation as the attack rate in controls is more likely to approach 100 percent).
Because of the remoteness of the geographic location, the duration of local exposure (approximately 5–6 months) and the other demands of participating in an intensive, complex vaccine trial, a dropout rate (loss to follow-up) of up to 18 percent must be expected.
A total of 164 analyzable subjects per group is needed to have 90 percent power to detect a significant difference (alpha = 0.025, single tail) if the expected attack rate in controls is 70 percent and expected vaccine efficacy is 60 percent (with a lower limit of 30 percent for the 95 percent CI). If 200 subjects are randomly allocated to the malaria vaccine group and 200 to the control group, with 18 percent loss to follow-up, at the end of the study there will remain approximately 164 vaccine and 164 control subjects available for analysis. At the expected attack rate, this would yield about 115 confirmed P. falciparum cases among the controls and about 46 cases among the vaccinees (60 percent proportionate reduction); the 161 cases in this scenario would provide the total of 160 cases needed to address the primary aim. With these results as an example, the 95 percent CI around the 60 percent point estimate of vaccine efficacy would be 43 percent lower limit and 72 percent upper limit.
If this first phase 3 efficacy trial in subjects not under cover of chemoprophylaxis is successful, the committee proposed that a corroborating trial of identical design be carried out one season later. This trial would provide a second opportunity to collect clinical specimens in the search for immunologic correlates of protection.
If the corroborating phase 3 trial not under chemoprophylaxis also yields positive results, it would be appropriate for the Military Infectious Diseases Research Program (MIDRP) Malaria Vaccine Program to undertake a much larger phase 3 trial with 10 times as many subjects in the