Placebo control still has important place in clinical research
Even a failed clinical trial can have valuable lessons. That’s the message investigators are taking from a randomized, double blind trial of a candidate therapeutic vaccine against HIV — which found no discernible benefit from the product relative to placebo.
Indeed, that’s one of the lessons — that placebo control remains an important part of clinical studies, according to lead investigator Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID).
Results from the vaccine arm of the study appearing in Science Translational Medicine, were so good that in the absence of a placebo group, the researchers “would have assumed incorrectly” — on the basis of historical data — that the drug had worked, Fauci said in an audio statement.
Investigators often worry about the safety of volunteers in the placebo arms of HIV trials, especially when the study involves stopping antiretroviral therapy (ART), as it did in this case.
But Fauci and colleagues noted that a recent single-arm study of a candidate therapeutic vaccine combined with the histone deacetylase inhibitor romidepsin showed that about 38% of HIV-positive volunteers were able to control their virus for a median of 14 weeks without ART.
Compared with historical data, that suggested at least some efficacy for the combination. But Fauci’s group noted that in their trial, 40% of the placebo patients would have met the same benchmark for viral control — almost identical to the other study but with no intervention at all.
The use of placebo control, blinding, and randomization is often controversial, commented Nelson Michael, MD, PhD, of the Military HIV Research Program at the Walter Reed Army Institute of Research, in Silver Spring, Maryland.
“In certain cases, the scientific and general community might feel that the use of any one or more of these clinical trial constraints is not ethically justified,” Michael argued in an accompanying Focus article.
But not using them can lead to wasted effort and even incorrect and dangerous conclusions about the efficacy of a given intervention, he stated.
The advent of antiretroviral therapy has allowed many people with HIV to live nearly normal lives but it’s still not possible to eradicate the virus, meaning patients are faced with a lifetime of therapy, with concomitant expense and side effects.
A therapeutic vaccine — a drug that would stimulate the immune system to control HIV without ART — is one theoretical way to avoid lifelong ART, but so far none has been successful, the researchers noted.
Fauci’s group had some hope of success. Their vaccine regimen included several HIV antigens, delivered in two different ways, in a prime-boost model. It included molecules known to stimulate the immune system. One component was given through in vivo electroporation, which has been shown to enhance the potency of the immune stimulation. And the trial participants were patients who had begun ART very soon after infection and were thought to have a “relatively preserved” immune system.
They enrolled 31 patients, all with HIV well controlled by ART, and randomly assigned them to the vaccine or placebo. One participant dropped out before the end of the vaccine phase of the study and was not included in the analysis.
The vaccine regimen itself had two components — a DNA plasmid encoding multiple HIV proteins combined with a DNA plasmid encoding two human interleukin-12 proteins as immune stimulants, as well as an attenuated live viral vector containing the HIV gag gene.
The DNA plasmids were given at weeks 0, 4, 12, and 36, while the viral vector was delivered at weeks 24 and 48. At study week 56, 2 months after the last injection, the patients stopped their ART for a planned 16 weeks.
The primary endpoints of the study were the safety of the regimen, and its ability to allow patients to suppress HIV replication in the absence of therapy, as measured by levels of viral rebound after patients stopped ART.
The safety of the vaccine regimen was established: the most common adverse events were transient low-grade pain or tenderness at the injection site or mild-to-moderate transient symptoms such as fatigue, myalgia, and arthralgia. Nobody stopped therapy owing to vaccine-related symptoms and there were no grade 3 or higher events related to the injections.
On the other hand, there was also no sign of efficacy, Fauci’s group reported.
Compared with placebo, the regimen had “no significant effect on the kinetics or magnitude of viral rebound after interruption of ART,” they said.
The median time from stopping ART to a viral load of more than 40 copies of HIV RNA/ml of plasma was 28 days in each arm. Similarly, the median time to more than 400 copies/ml was 28 in the vaccine arm and 30 days in the placebo arm. The proportion of study visits with viral load of fewer than 400 copies/ml was the same in each arm.
Importantly, they found, 26% of participants in the placebo arm had sustained HIV suppression (to fewer than 400 copies/ml) after they stopped ART — a rate markedly higher than previously reported.
Aside from the value of control groups, the researchers noted, the study also adds to the evidence that the key to a successful therapeutic vaccine will be its ability to stimulate CD8-positive T cell responses to the HIV gag protein.
In this study, they saw “little augmentation” of CD8 responses.
The study was supported by NIAID. One co-author is a NIAID employee. Some co-authors disclosed relevant relationships with Profectus BioSciencediscls.
Michael disclosed no relevant relationships with industry.
By Michael Smith
Science Translational Medicine
Source Reference: Sneller MC, et al “A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection” Sci Transl Med 2017; 9: eaan8848.
Science Translational Medicine
Source Reference: Michael NL “Clinical trial design: The nobility of randomization” Sci Transl Med 2017; 9: eaaq0810.