[afro-nets] Looking back at trial closures over the past year

[Omololu Falobi <omololu@nigeria-aids.org>]

Looking back at trial closures over the past year
-------------------------------------------------

The Global Campaign for Microbicides has compiled this useful report 
that discusses the closure of several new HIV prevention trials in 
Africa in the past year - including studies in four sites that closed 
in Nigeria alone (three of which occurred in the last one month).

The compilation provides a reflective analysis on the various difficult 
circumstances that can make or mar effectiveness of trials and study 
findings. Should be interesting reading for everyone - scientist, 
advocate, trial participant, sponsor or regulator.

Omololu Falobi
mailto:omololu@nigeria-aids.org

---

Global Campaign News - Issue #70
22 September 2006
Trials Watch

Looking back at trial closures over the past year

Africa

In the past two years, six important HIV prevention trials - two in 
Nigeria and one each in Cambodia, Cameroon, Ghana, and Malawi - have 
been shut down early, stopped before they began, or shifted enrollment 
to new sites. While all the trials were attempting to evaluate the 
effectiveness of either microbicides or oral tenofovir as pre-exposure 
prophylaxis (PREP), it is important to recognize that they were 
discontinued for very different reasons.

SAVVY GHANA TRIAL
In November 2005, Family Health International (FHI) and Cellegy 
Pharmaceuticals announced plans to discontinue an on-going Phase III 
study of the effectiveness of Savvy, a candidate microbicide.

In the Savvy Ghana trial, HIV incidence in the study population was too 
low to show whether use of Savvy, compared with a placebo gel, would 
prevent HIV. It was deemed impossible to expand or extend recruitment 
sufficiently at the Ghana sites to make up for the lower than expected 
incidence. There were just not enough eligible women in these settings 
to make expansion feasible.

The relatively low overall incidence suggested that condom counseling, 
HIV testing, and other prevention interventions provided to 
participants may have contributed to a reduction in the number of HIV 
infections. These findings represent a public health success, but such 
low incidence meant that the study could no longer answer the question 
about product effectiveness.

SAVVY NIGERIA TRIAL
Almost a year later in September 2006, FHI and Cellegy announced the 
premature closure of a second Savvy trial, this one taking place in 
Nigeria. While HIV incidence in the study population was also lower 
than anticipated, the decision to close this study had a different 
rationale. The independent Data Monitoring Committee (DMC) recommended 
discontinuing the study because interim review of the unblinded data 
suggested that there was no evidence that Savvy was reducing risk of 
HIV transmission. If they had found evidence of a protective effect, 
investigators could have extended the trial and enrolled more women in 
order to compensate for the lower than expected incidence rate. In both 
studies the rates of side effects were similar between the product and 
placebo groups, and study participants experienced no serious medical 
problems deemed related to product use.

To date, nearly 70 percent of the women in the Savvy Nigeria study 
currently in follow-up have completed all their planned visits. The FHI 
study team plans to inform each woman who has not already completed the 
study about the study closure at her next scheduled follow-up visit, 
when she will receive a final HIV test. In short, they will follow the 
same, standard study procedures that were used with participants who 
have already completed the study. These procedures have been reviewed 
and approved by the local ethical review committee and Nigeria's 
national drug agency, the National Agency for Food, Drug Administration 
and Control (NAFDAC).

The study clinics will remain open until 15 December 2006 so that study 
participants can come in for additional counseling, information, test 
results, and condoms. Once all the remaining follow-up visits have been 
completed, FHI will analyze the data and report the study results to 
the local and international community.

The site investigators have written agreements in place with the local 
PEPFAR programs to provide care to participants who tested HIV-positive 
during the study, including antiretroviral treatment as needed.

Given that these two large studies failed to provide even preliminary 
evidence of Savvy's effectiveness against HIV, it is unlikely that 
sponsors will pursue further research on Savvy as a potential 
microbicide. Other organizations are continuing to conduct trials in 
the United States to determine if Savvy is effective as a 
contraceptive.


CELLULOSE SULFATE NIGERIA TRIAL
This month FHI, CONRAD and USAID made a joint study management decision 
to expand their Phase 3 trial of cellulose sulfate to a second country 
in sub-Saharan Africa while ending recruitment of new participants in 
Nigeria. Follow-up will be completed in Nigeria for the nearly 1,600 
women already enrolled in the study.

This decision was made after a review by the study's independent DMC, 
conducted on 5 September, found that no serious symptoms or medical 
conditions were associated with gel use, leading to the DMC 
recommendation to continue the trial. In this case the interim analysis 
examined only safety data, as required by the study protocol, and not 
effectiveness data.

This trial was designed to enroll over 2,100 Nigerian women at sites in 
Lagos and Port Harcourt. At trial initiation, the anticipated HIV 
incidence in this population was 3.75 percent. By August 2006, with 
about 70 percent of planned enrollment completed, overall annual HIV 
incidence among study participants was less than 2 percent. 
Lower-than-anticipated incidence means that the size of the study needs 
to increase to ensure that results will be statistically significant. 
Based in part on instability in the oil-producing Delta region of the 
country, where one of the research sites is located, FHI determined 
that the most efficient way to complete the study was to expand to 
another site with high HIV incidence outside of Nigeria.

As the study continues in Nigeria, any women who seroconvert will 
continue to be referred to PEPFAR programs in Lagos or 
government-subsidized programs in Port Harcourt that have agreed to 
provide them care and antiretroviral treatment when needed. A written 
agreement is also in place with the PEPFAR centers in Lagos to provide 
these services free of charge to participants from Port Harcourt if 
they are willing to relocate.

A similar (but separate) study of cellulose sulfate is continuing in 
Benin, Burkina Faso, India, South Africa, and Uganda sponsored by 
CONRAD.

ORAL TENOFOVIR TRIALS
As described in previous issues of GC News, four other trials 
evaluating once-a-day use of tenofovir for oral prophylaxis have also 
been suspended in the last 2 years - Cambodia, Cameroon, Malawi and 
Nigeria. Again the reasons behind these closures vary by site. The 
Cambodian and Cameroonian studies were both subject to intense media 
criticism and controversy due to ethical concerns raised by activist 
groups. These closures were due to unresolved controversy. By contrast, 
the Nigerian trial of oral tenofovir did not close due to protest, but 
because of data irregularities and other technical problems. The Malawi 
study was suspended before it began because concerns were raised that 
the use of tenofovir for oral prevention might undermine its utility as 
an HIV treatment drug.

In Nigeria, the women who became infected during the trial were 
referred to PEPFAR programs for care and treatment. In Cameroon, study 
staff offered those who seroconverted referrals to, and assistance 
accessing if needed, HIV-related psychological, social and medical 
services in their communities. These services include tenofovir 
resistance, viral load and CD4 level testing and antiretroviral drug 
provision when indicated. In both Malawi and Cambodia, no women 
serocoverted because the trials never began enrolling.

FHI releases combined preliminary results from several oral Tenofovir 
studies

Tenofovir--well-known in HIV/AIDS treatment circles--has been used for 
years as one of many treatment options for those living with HIV/AIDS. 
The drug has received increased attention recently as researchers have 
worked to expand its use from HIV treatment to HIV prevention. The hope 
is that tenofovir could help reduce the risk of acquiring HIV if taken 
once a day as a "prevention pill" -a strategy known as pre-exposure 
prophylaxsis (PREP).

As discussed above, the attention given to tenofovir has not always 
been positive, however. Most notably, two oral tenofovir trials, one in 
Cameroon and one in Cambodia, came under harsh criticism from the media 
and activists due in part to inaccurate press coverage and unresolved 
issues around standard of care for trial participants. The Cambodian 
trial was suspended before it formally began in August 2004 and the 
Cameroon trial was shutdown in 2005. Nonetheless, researchers and 
advocates have re-committed themselves to working together to ensure 
the ethical and safe completion of future PREP trials.

At the 16th International AIDS Conference in Toronto last month, Family 
Health International (FHI) released preliminary findings from the 
combined results of the oral tenofovir studies they conducted in Ghana, 
Nigeria and Cameroon. Because the Nigerian and Cameroonian studies were 
closed early, and because the trials experienced lower than expected 
HIV incidence, there were too few HIV infections to draw conclusions 
regarding the effectiveness of tenofovir for oral prevention. 
Nonetheless, the combined data demonstrated that oral tenofovir (or 
Viread as it is manufactured and marketed by Gilead) appeared safe and 
was generally well tolerated. Importantly, there were no significant 
differences in liver or kidney functioning between individuals who 
received tenofovir and those who received a placebo.

Overall HIV infections occurred in two women taking Viread, and in six 
women taking the placebo. But scientists warn that given the small 
number of infections involved, these findings should not be 
over-interpreted. As lead investigator, Dr. Ward Cates of FHI observed 
in the Wall Street Journal, "Because the numbers were low, we could 
have observed this [infection rate] by chance. It's important that we 
have additional studies to determine if it is effective and, if so, how 
effective".

Additional studies are currently underway with funding from the U.S. 
Centers for Disease Control & Prevention (CDC) and the National 
Institutes of Health (NIH) to determine whether tenofovir (or other 
PREP regimens) will be effective in preventing the transmission of HIV. 
CDC studies are planned or underway in Thailand, Botswana and the U.S., 
and a NIH sponsored study will soon begin enrolling MSM in Peru.