CPCRA CMV Study CPCRA 023: Questions and Answers.
1. What was the CPCRA CMV Study?
The CMV protocol conducted by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), was a multicenter, randomized, double-blind clinical trial that compared oral ganciclovir with placebo for the prevention of symptomatic CMV disease of the retina or gastrointestinal tract.
2. What was the purpose of the CPCRA CMV Study?
The primary intent of this study was to determine whether oral ganciclovir was safe and effective for the prevention of symptomatic CMV disease. Other objectives were to determine if oral ganciclovir improved survival and quality of life as compared to placebo.
3. Who was eligible to participate in the study?
Patients with a CD4+ count of 100 cells/mm3 or lower who had a positive CMV serology or culture but not CMV disease.
4. Where and when was this study conducted?
This study was conducted at 16 units of the CPCRA. The study opened for enrollment in April 1993 and finished accrual on June 3, 1994 after enrolling 144 more patients than was originally planned (994 instead of 850). All patients were followed for a minimum of 1 year and the study was closed on schedule on June 3, 1995.
5. Who sponsored the study?
This study was sponsored by the CPCRA of the National Institute of Allergies and Infectious Diseases (NIAID). NIAID established the CPCRA in 1989. The program includes groups of primary care physicians and nurses who care for large numbers of people with HIV infection, and who work in community health centers and hospitals, private clinics or practices, and drug treatment facilities.
6. What dosage of oral ganciclovir was used?
Oral ganciclovir, provided by Syntex Research, Palo Alto, California, was supplied as 250 mg capsules. Patient were instructed to take 3 grams of ganciclovir or matching placebo each day (4 capsules 3 times per day).
7. How was the primary endpoint of the study, symptomatic CMV disease, defined?
The primary endpoint of the study, symptomatic CMV disease, was defined as either confirmed CMV retinal disease or confirmed gastrointestinal mucosal disease. Confirmation of retinitis required a dilated ophthalmoscopic examination conducted by an ophthalmologist. Confirmation of CMV gastrointestinal disease required histopathologic evidence of CMV inclusion bodies biopsy or autopsy.
8. How were patients randomized to treatment groups?
When a patient was identified as eligible for the study, a research nurse called the Statistical center for the treatment assignment code - ganciclovir or placebo. An eligibility checklist was reviewed before randomization. Twice as many patients were randomized to receive ganciclovir as compared to placebo. When enrollment was stopped, 662 patients had been randomly allocated to receive ganciclovir and 332 had been allocated to receive placebo.
9. What does it meant that the study was conducted double-blind? Double-blind means that neither the patients nor the clinicians knew if an individual patient was receiving ganciclovir or placebo. Placebo capsules were made to look identical to the active drug. This information was kept confidential by the Statistical Center until the close of the study.
10. What were the results of the study?
We found that 3 grams daily of oral ganciclovir did not prevent symptomatic CMV disease or improve quality of life. There was a suggestion for a modest survival benefit for those who were assigned ganciclovir, but it was not statistically significant. Thus the suggested survival difference could be a chance finding. More patients assigned ganciclovir than placebo had adverse experiences.
11. What was the most common toxicity?
A low neutrophil count (less than 750) was the most common toxicity.
12. Was the study reviewed by a Data and Safety Monitoring Board during its conduct?
Yes, the study was reviewed by a Data and Safety Monitoring Board (DMSB) which is advisory to the Division of AIDS (DAIDS) of NIAID. It was reviewed on six occasions. On one occasion, in July, 1994, a protocol change was recommended which was implemented in September 1994.
13. What protocol change was recommended by the DSMB and why was it made?
In July 1994, The DSMB recommended that CPCRA patients be informed of the results of another study on oral ganciclovir that was being conducted by Syntex Research. That study, which was called Syntex 1654, also compared oral ganciclovir with placebo for prevention CMV disease. Based on an interim analysis which showed substantial and significant benefit for oral ganciclovir in preventing CMV disease compared to placebo, Syntex 1654 was stopped. There was also a trend for increase survival in the ganciclovir group in Syntex 1654. The DSMB for the CPCRA CMV study recommended that CPCRA patients be continued on blinded medication provided that they were informed of the results of the Syntex study and of the current assessment of the CPCRA study. At reconsent, patients who had not experienced CMV and who had not had study medication discontinued for toxicity were offered the option of switching to open-label oral ganciclovir.
14. What did the DSMB recommend that CPCRA patients continue on blinded medication?
In July 1994, the interim results of the CPCRA study (like the final results) differed substantially form those of the Syntex study. In the CPCRA study, a similar percentage of patients assigned ganciclovir and placebo had developed CMV and there was no evidence of a survival advantage for ganciclovir. In fact, at that time (July 1994), there was a trend toward higher mortality rates in the ganciclovir group. Since there was no indication that ganciclovir was beneficial and since the primary endpoint of the Syntex study was ascertained differently from the CPCRA study, the DSMB felt if was important to continue the CPCRA study in order to understand whether ganciclovir was beneficial.
15. How did the Syntex CMV Study and CPCRA Study differ in their design?
The most important difference between the two studies is how the CMV disease endpoint was determined. In the Syntex study, patients had a bi-monthly dilated fundoscopic examination performed by a study ophthalmologist. In the CPCRA CMV study, patients were not required to be seen by an ophthalmologist until they had symptoms. As a consequence of the screening performed in the Syntex study, about twice as many patients were diagnosed wit CMV retinal disease. We presumed that much of the CMV disease in the Syntex study was diagnosed before symptoms emerged. Another difference, which is less important, was that in the Syntex CMV study patients with a CD4+ count between 50 and 100 cells/mm3 also had to have a history of an AIDS-defining opportunistic infection. In the CPCRA CMV study that was not a requirement.
16. How do the results of this study influence patient care?
The results of our study do not support the use of oral ganciclovir for the prevention of CMV disease.
17. Is oral ganciclovir available for use as a prophylaxis for CMV?
Oral ganciclovir is not currently licensed for use as prophylaxis for CMV disease. A decision on licensure is expected in 1996. Patients in the CPCRA CMV study may obtain oral ganciclovir without charge though an expanded access program that Syntex has offered. This program is called GANS2648, "An Open-Label Study of the Safety of Oral Ganciclovir for the Prevention of CMV Disease in People Infected with the Human Immunodeficiency Virus". Since the Syntex randomized trial differs markedly from the CPCRA study, some clinicians and patients may choose to enroll in the expanded access program.