Public Health

7 Clinical Trials That May Change Your Practice

Author:
Robin K. Avery, MD
Johns Hopkins Medicine

Citation:
Avery RK. 7 clinical trials that may change your practice [published online October 16, 2019]. Infectious Diseases Consultant.


 

During my session at IDWeek 2019, I discussed 6 published trials and one in-progress trial of viral diseases that may change the way we practice infectious disease care. The first 3 trials pertain to cytomegalovirus (CMV) infection in transplant recipients, the next 3 pertain to immunizations in immunocompromised hosts, and the last pertains to an underdiagnosed infection in transplant recipients.

Papanicolaou GA, Silveira FP, Langston AA, et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Clin Infect Dis. 2019;68(8):1255-1264. https://doi.org/10.1093/cid/ciy706.

Despite advances in CMV prevention, there are still cases of complex CMV syndromes that can be devastating for transplant recipients. Ganciclovir and valganciclovir have been the main drugs used for prophylaxis and therapy for many years, but they often cause cytopenias, and may not work; the traditional options for treating resistant/refractory CMV (foscarnet and cidofovir) are nephrotoxic and are associated with suboptimal virologic responses as well as a lot of toxicity. So there has long been a need for a drug that lacks the hematologic toxicities of ganciclovir/valganciclovir and the nephrotoxicity of foscarnet and cidofovir. Maribavir is an oral investigational anti-CMV drug that lacks major organ toxicities; its major adverse effect is dysgeusia (which can persist beyond the dose), and the second most common adverse effect is nausea.

Genovefa A. Papanicolaou and colleagues conducted a phase 2, 3-arm, blinded, dose ranging trial of 3 doses of maribavir in 120 patients undergoing solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) with resistant/refractory CMV. Results were similar across all doses and showed essentially a two-thirds response rate in terms of clearing viremia, an encouraging result in this group who had failed prior therapies. There was a 35% recurrence rate, not surprising, since recurrence is often a feature of resistant/refractory CMV.

Take-Home Message: Maribavir, currently an investigational drug, is a potentially valuable addition to the CMV armamentarium, both in terms of its efficacy and lack of major organ toxicity, and currently is the only drug being specifically developed for treatment of resistant/refractory CMV. A phase 3 trial in resistant/refractory CMV is in progress, with a 2:1 open-label randomization to maribavir versus investigator-assigned therapy, so there is a non-maribavir comparator arm (eg, foscarnet, etc). We hope that maribavir will be available for clinical use in the future, as we need as many treatments for resistant/refractory CMV as we can get. 

Maertens J, Cordonnier C, Jaksch P, et al. Maribavir for preemptive treatment of cytomegalovirus reactivation. N Engl J Med. 2019:381(12):1136-1147. https://doi.org/10.1056/NEJMoa1714656.

This was a phase 2 study conducted in Europe at the same time as Papanicolaou and colleagues’ study. It was an open-label, randomized, 4-arm trial of 3 doses of maribavir versus valganciclovir for uncomplicated CMV viremia in SOT and HSCT recipients. Efficacy in terms of clearance of viremia was similar between the 2 drugs, and the maribavir groups, as expected, demonstrated a lower incidence of neutropenia than valganciclovir, though a higher incidence of gastrointestinal adverse effects and higher drop-out rate on this basis was observed. Among HSCT recipients, a greater percentage of patients cleared viremia within 6 weeks in the maribavir groups compared with the valganciclovir groups.

Take-Home Message: Maribavir and valganciclovir are both effective antiviral agents for pre-emptive therapy of uncomplicated CMV viremia. Maribavir may provide the long-awaited non-neutropenia-producing alternative for pre-emptive therapy in SOT and HSCT recipients, especially those who are already cytopenic when CMV develops, but maybe not in patients who already have severe nausea. Having more than one oral drug available for CMV treatment would be beneficial for patients; clinicians could then decide which patients would do best with which treatment.

Ljungman P, Schmitt M, Marty FM, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation [published online June 8, 2019). Clin Infect Dis. https://doi.org/10.1093/cid/ciz490.

This study is an updated mortality analysis of the study subjects from the 2017 phase 3 HSCT prophylaxis trial,1 as the authors had obtained more complete and updated outcomes data at the later time points of the study. Traditionally, HSCT programs have favored pre-emptive therapy (CMV polymerase chain reaction [PCR] monitoring and treatment only when the CMV PCR rises to a prespecified level) instead of prophylaxis (in which everyone gets an antiviral); this is because the existing oral drug was valganciclovir, which was associated with high risk for neutropenia in the HSCT population and hence, pre-emptive therapy was favored. However, with the development of letermovir, there is now the potential for prophylaxis with a drug that does not cause hematologic toxicity. In the 2017 NEJM paper,1 which led to the approval of letermovir by the U.S Food and Drug Administration (FDA) and European Medicines Agency (EMA) for HSCT prophylaxis,  the outcome measure of “clinically significant CMV infection” was significantly lower (though not zero) in the letermovir prophylaxis group versus the group managed with conventional monitoring of CMV PCR and valganciclovir/ganciclovir therapy if CMV occurred.

The updated mortality analysis  (which was the trial I selected for this presentation, not the parent trial from 2017) demonstrated that the hazard ratio for all-cause mortality was 0.58 at week 24 (95% CI, 0.35–0.98; P = .04) and 0.74 at week 48 (95% CI, 0.49–1.11; P = .14). For patients in the letermovir arm, there was no difference in mortality between those who had and those who did not have clinically significant CMV infection. In the placebo arm, though, there was a higher mortality in those with CMV versus those without CMV. Finally, when CMV infection did occur in the letermovir arm, it was further out in time (mainly after completion of the 14-week prophylaxis), leading the authors to suggest that there is an advantage to delaying the onset of CMV infection until more immune reconstitution has occurred. Consequently, another ongoing trial is examining prolonged letermovir prophylaxis (200 versus 100 days) to see if even more benefit can be achieved.

Take-Home Message: The authors concluded that letermovir may reduce mortality by preventing or delaying clinically significant CMV infection after HSCT. If CMV infection is prevented until a later time point when the immune system is better able to handle CMV reactivation, this may be less harmful than reactivation earlier in the course of the transplant. This is also accomplished without causing cytopenias. This provides an additional motivation for HSCT programs to use letermovir prophylaxis.

Natori Y, Shiotsuka M, Slomovic J, et al. A double-blind, randomized trial of high-dose vs standard-dose influenza vaccine in adult solid-organ transplant recipients. Clin Infect Dis. 2018;66(11):1698-1704. https://doi.org/10.1093/cid/cix1082.

I started by commending Deepali Kumar and colleagues at the University of Toronto for many years of performing rigorous, informative studies of immunizations in the SOT population. This study by Yoichiro Natori and colleagues examined vaccine responses to 1, 2, or all 3 antigens after receiving seasonal influenza vaccine, in 172 adult SOT recipients randomized to either standard-dose or high-dose vaccine.  Influenza can have devastating consequences for transplant recipients, and influenza vaccination is important but not always effective in this population. Consequently, any interventions that can improve vaccine responses are potentially very important. In the United States, the high-dose influenza vaccine is approved for older individuals. However, the data in this study suggest that all adult SOT recipients can benefit from the high-dose vaccine, as it is more immunogenic both in terms of the percentage of patients who respond to 1, 2, and 3 antigens and also the geometric mean titers after immunization. A follow-up study by the same group compared the T-cell immune responses and also found superior responses with the high-dose vaccine.2

Take-Home Message:  Transplant programs should consider recommending the high-dose influenza vaccine for all SOT recipients, based on the humoral and cellular immune response data in this study. Insurance coverage may be an issue in the United States for younger patients.

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Vink P, Torrell JMR, Sanchez Fructuoso A, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in chronically immunosuppressed adults following renal transplant: a phase 3, randomized clinical trial [published online March 7, 2019]. Clin Infect Dis. https://doi.org/10.1093/cid/ciz177.

The recombinant zoster vaccine (RZV, consisting of a form of glycoprotein E plus a novel adjuvant) is currently recommended in the United States as 2 doses for immunocompetent individuals aged 50 or older. The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has not yet issued a recommendation regarding RZV for immunocompromised patients. The older, live zoster vaccine is not indicated for post-transplant patients, since it is a live vaccine, so the safety and efficacy of RZV in SOT recipients is potentially of great interest. Data are beginning to emerge in the immunocompromised population. This study was a randomized placebo-controlled trial of 264 kidney transplant recipients, who received 2 doses of RZV between 4 and 18 months post-transplant. Humoral and cellular immunogenicity was assayed, and the humoral vaccine response rate was 80%, while the viral response rate (VRR) was 71.4% for cellular responses (measured in a subset of study patients). As in other studies of RZV, local reactions were much more common than with placebo. However, there were no safety concerns in terms of major adverse events. Importantly, there was no increased incidence of rejection or of worsening renal function in the RZV group.

Take-Home Message: In addition to demonstrating immunogenicity in an immunocompromised population, this study allays some of the initial theoretical concerns about RZV in organ transplant—namely whether the novel adjuvant might trigger nonspecific immune activation—and, hence, whether this vaccine might possibly increase the incidence of allograft rejection. Although vaccines in general do not trigger rejection in organ transplant recipients, this is a novel adjuvant, and therefore, it was important that the study found that there were no major safety concerns and, in particular, no excess rejection nor allograft dysfunction/

Bastidas A, de la Serna J, El Idrissi M, et al; ZOE-HSCT Study Group Collaborators. Effect of recombinant zoster vaccine on incidence of herpes zoster after autologous stem cell transplantation: a randomized clinical trial. JAMA. 2019;322(2):123-133. https://doi.org/10.1001/jama.2019.9053.

Like the previous study I discussed, this study of RZV in recipients of autologous HSCT is an important further step toward understanding the safety and efficacy of RZV in immunocompromised patients. Of all immunocompromised patients, HSCT recipients have the highest risk for zoster, and many are consequently treated with prolonged antiviral prophylaxis. In this randomized, placebo-controlled autologous HSCT study in more than 1800 patients, not only immunogenicity but also efficacy in terms of clinical zoster outcomes was reported. An incidence rate ratio for zoster of 0.32 was observed (equivalent to a 68% vaccine efficacy). However, the first dose of RZV was given at 50 to 70 days post-transplant, whereas other immunizations are generally started later. So it is possible that the efficacy might be even higher when administered further out in time from transplant. In addition to zoster incidence, the investigators reported other zoster complications including post-herpetic neuralgia and duration of worst zoster pain, and both showed significant reductions.

Take-Home Message: RZV significantly reduced the incidence of zoster after autologous HSCT, and reduced postherpetic neuralgia and other zoster complications. There were no major safety concerns. Questions include whether the efficacy of the vaccine is high enough to induce HSCT programs to discontinue prolonged antiviral prophylaxis after autologous HSCT, and whether the efficacy might be even higher if the vaccine was given later in time post-transplant. Finally, it is worth noting that this study was done in autologous, not allogeneic, HSCT recipients, and the theoretical risk of graft-versus-host disease (GVHD) being triggered by nonspecific immune activation is not an issue with autologous HSCT. Therefore, more data in allogenic HSCT recipients would be valuable. Overall, however, the two studies cited here in kidney transplant and autologous HSCT recipients are quite reassuring as to safety in the populations that were enrolled.

Randomized, Double-Blind Study to Assess the Clinical and Antiviral Efficacy and Safety of Nitazoxanide for the Treatment of Norovirus in Hematopoietic Stem Cell and Solid Organ Transplant Recipients. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03395405. Accessed October 15, 2019. ClinicalTrials.gov identifier NCT03395405.

This is a randomized, placebo-controlled, double-blind multicenter study of nitazoxanide for treatment of norovirus infection in transplant recipients. Severe chronic norovirus infection has been identified as an increasing, but underdiagnosed, complication after transplant and is frequently associated with lengthy relapsing courses, weight loss, renal dysfunction, and malnutrition. There are no licensed drugs currently available for treatment of norovirus, but anecdotally, responses to off-label nitazoxanide have been reported. The current study incorporates not only sequential stool sampling and virologic assessments, but also patient-reported outcomes.

Take Home Message: I included this study, though it is a study in progress, because I feel it is really important to educate clinicians (including infectious disease specialists, transplant clinicians, primary care clinicians, and gastroenterologists) to look for this syndrome in immunocompromised patients with chronic diarrhea. I also wanted to deputize everyone in the meeting room to go and tell their colleagues about this underdiagnosed entity of severe chronic norovirus infection. Too often, patients have undergone multiple evaluations including colonoscopies and have continued to worsen, without ever being tested for norovirus. I commended Mike Ison and the centers involved in this study for trying to study this rigorously, and we are looking forward to the results!

Robin K. Avery, MD, is a professor of medicine in the Division of Infectious Diseases at Johns Hopkins Medicine in Baltimore, Maryland.

References:

  1. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;2017;377(25):2433-2444. https://doi.org/10.1056/NEJMoa1706640.
  2. L'Huillier AG, Ferreira VH, Hirzel C, et al. Cell-mediated immune responses after influenza vaccination of solid organ transplant recipients: a secondary outcomes analysis of a randomized controlled trial [published online September 24, 2019]. J Infect Dis. https://doi.org/10.1093/infdis/jiz471.