September 21, 2012
The COAT trial was designed as a Phase IV, randomized clinical trial to compare the 26-week survival difference for early versus standard initiation of ART among HIV-infected individuals with CM.
Study volunteers were randomly assigned to start ART as an inpatient after 7 to 11 days of receiving amphotericin plus fluconazole 800mg/day anti-fungal treatment for CM (early arm); or start ART five weeks following hospital discharge according to standard practice(standard arm).
Antiretroviral therapy consisted of an efavirenz -based regimen and two nucleoside reverse transcriptase inhibitors (NRTIs) in accordance with national guidelines for Uganda and South Africa.
Cryptococcal meningitis (CM) is a fungal infection of the brain and spinal cord. The disease is caused by Cryptococcus neoformans (C. neoformans), a type of fungus found in soil throughout the world, often in association with bird droppings. Exposure occurs by inhaling microscopic fungal spores that have become airborne. Clinical disease occurs most often in persons with suppressed immune systems, such as in HIV/AIDS.
Each year, an estimated 1 million people worldwide are infected with CM, resulting in nearly 600,000 deaths. CM is also one of the most common HIV-related opportunistic infections worldwide, and is the most common cause of meningitis in Africa. CM accounts for between 13 to 44 percent of deaths in HIV-infected individuals living in resource-limited countries. Specifically, in sub-Saharan Africa alone, there are approximately 500,000 deaths each year due to CM.
On April 18 and April 27, 2012, an independent data and safety monitoring board (DSMB) reviewed interim study data obtained from 174 participants. Of that number, 87 participants were assigned to receive early ART compared to the 87 participants assigned to receive delayed HIV treatment. The DSMB recommended that the trial discontinue enrolling new participants because it found higher mortality rates among participants assigned to the early ART arm (42.5 percent mortality in the early arm compared to 27.6 percent mortality in the standard arm).
In evaluating data from the 174 study participants the DSMB found that those who were randomized to receive early ART were approximately 1.7 times more likely to have worse survival at any one point compared to participants who were randomized to receive delayed ART. The difference in the mortality was more evident in participants with a Glasgow Coma Scale (GCS) lower than 15, especially in the period between 8 and 30 days after randomization. Furthermore, the study showed no evidence of benefit of early ART in participants with a normal mental status at time of study enrollment (GCS equal to 15). The GCS was used by the study to help assess mental status by measuring eye, verbal, and motor responses. Based on these findings, the DSMB determined that the trial would be unlikely to show a significant survival benefit through early ART intervention, and therefore, recommended that enrollment in the study end.
NIAID concurred with the DSMB’s recommendation. Participants continue to be followed by study staff, according to the trial protocol. The study data will continue to be collected through patient follow up and will be made publicly available after the trial officially concludes in 2015.
When new enrollment into the trial was stopped, participants who had been recently enrolled in the early arm were contacted and evaluated immediately. Although the COAT trial discontinued enrolling new participants, all participants will continue to be seen at their study sites for up to 46 weeks for tests and procedures as specified in the protocol. The DSMB’s findings and their impact on individual HIV treatment management were discussed with participants.
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Last Updated September 21, 2012
Last Reviewed September 21, 2012