Four notable phase 4 trials

By Naveed Saleh, MD, MS
Published January 21, 2022

Key Takeaways

  • Phase 4 trials provide long-term looks at the safety and efficacy of drugs.

  • These trials often require years and thousands of participants to complete.

  • Recent standout Phase 4 trials covered hepatitis C, organ transplant, cerebrovascular disease, and COVID-19.

Phase 3 trials tend to steal the spotlight. After all, this is the gateway through which all drugs must pass for FDA approval. However, phase 4 trials—which delve into patient quality of life and cost effectiveness—often offer some fascinating insights. Phase 4 findings, for example, could change efficacy and adverse effects parameters.

Clinicians can benefit from taking notice of recent phase 4 trials regarding a range of diseases.

Hepatitis C

Direct-acting antivirals have revolutionized the treatment of hepatitis C. Nevertheless, adoption of these agents—even in generic formulations—remains limited. Challenges include availability and access to diagnostic tools and monitoring, as well as the need for frequent follow-up and necessary infrastructure.

What is the MINMON approach?

The minimal monitoring (MINMON) approach consists of four components: 

  1. No pre-treatment genotyping

  2. Dispensing the entire treatment course (84 tablets) at entry

  3. No scheduled lab visits for monitoring

  4. Remote contact at week 2 and week 22, at which outcome assessment is scheduled at week 24

In a phase 4, open-label, single-arm trial spanning 38 global sites published in the Lancet Gastroenterology and Hepatology, researchers assessed the efficacy of the minimal monitoring (MINMON) approach, which entailed no pre-treatment genotyping, giving the entire oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks upfront, no scheduled labs, and limited office contact.

“In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda,” the authors wrote.

Related: Minimizing liver damage from prescription meds: The latest guidelines

Organ transplant

Following solid-organ transplant, the most common opportunistic infection is cytomegalovirus (CMV). In the results of a phase 4 multicenter trial published in the American Journal of Transplantation, researchers tested whether treatment with everolimus (EVR) reduced the incidence of CMV DNAemia and disease in 186 CMV seropositive kidney-transplant recipients. The patients were randomized evenly to receive S cyclosporin, and steroids. Of note, CMV DNAemia is a method of detecting CMV DNA in plasma, whole blood, or so forth.

"EVR prevents CMV DNAemia requiring treatment in seropositive recipients as long as it is tolerated and maintained."

American Journal of Transplantation

The researchers found that in the EVR group, fewer patients received CMV treatment. “EVR prevents CMV DNAemia requiring treatment in seropositive recipients as long as it is tolerated and maintained,” the authors wrote.

Cerebrovascular disease

Dipyridamole is a vasodilator and inhibits platelet aggregation. It decreases the risk of thromboembolism and repeat stroke in those with atherosclerotic cerebrovascular disease.

This agent works by inhibiting adenosine uptake by platelets and endothelial cells, stockpiling cAMP and stymieing the stimulation of platelet aggregation by platelet-activating factor and collagen.

In a phase 4 trial published in Cerebrovascular Disease, researchers analyzed the impact of gradual dipyridamole titration and the incidence of dipyridamole-induced headache in patients with ischemic stroke or transient ischemic attack (TIA).

The regimen involved Adinox (aspirin 25 mg/dipyridamole 200 mg) plus aspirin (100 mg) once daily for the initial 2 weeks followed by Adinox twice daily for 2 weeks (i.e., titration group), Adinox twice daily for 4 weeks (i.e., standard group), and aspirin 100 mg once daily for 4 weeks (i.e., control group).

The researchers found that the titration method decreased total dipyridamole-induced headache incidence over 4 weeks compared with the standard group, with adverse events more common in the standard group.

Related: Closing the communication gap between physicians and pharmacists


Concurrent inoculation with COVID-19 and the influenza seems like a no-brainer. But, this co-administration must be deemed safe first, which is why UK researchers analyzed the combination in a phase 4 trial.

They found that concurrent administration of the AstraZeneca or Moderna vaccines along with an age-appropriate influenza virus was safe and resulted in sustained antibody responses. 

“Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunization season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need,” researchers concluded.

What this means for you

Although Phase 3 trials get all the fanfare, Phase 4 trials reflect the long-term efficacy and safety of a drug. Once a drug hits the mass market, unanticipated effects may result, highlighting the need for clinicians to stay abreast of these trials.


  1. Kang MK. Effects of Dose Titration on Dipyridamole-Induced Headache: A Randomized, Double-Blind Clinical Trial. Cerebrovascular Diseases.

  2. Kiminski H. Incidence of cytomegalovirus infection in seropositive kidney transplant recipients treated with everolimus: A randomized, open-label, multicenter phase 4 trial. American Journal of Transplantation.

  3. Lazarus R. Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial. Lancet.

  4. Solomon SS. A minimal monitoring approach for the treatment of hepatitis C virus infection (ACTG A5360 [MINMON]): a phase 4, open-label, single-arm trial. Lancet Gastroenterology and Hepatology.

Share with emailShare to FacebookShare to LinkedInShare to Twitter