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Clinical Trials – And Errors?

Clinical Trials – And Errors?

By Randolph Fillmore

Around the world, clinical trials are getting underway to find a drug, or drugs – any drugs – that will act as a vaccine for preventing COVID-19, effectively treat its symptoms or, optimally, kill the virus in people who have tested positive for it so that the disease will not progress. Most of the new clinical trials are either for remdesivir, the drug developed to treat Ebola but was disappointing in its application, or hydroxychloroquine, a drug developed and used to treat the symptoms of malaria but has also  been found to be effective in treating the symptoms of both rheumatoid arthritis and Lupus, a long-term disease causing inflammation and pain. Both are non-viral, autoimmune diseases caused by the body’s immune system attacking healthy tissue.

Neither drug has seen widespread, scientific testing or used in connection with SARS-Coronavirus-2, the new virus causing COVID-19, and spreading death and misery worldwide for months. With the hope that either or both might be effective treatments, clinical trials are getting underway in the US and elsewhere.

What is a clinical trial?

A clinical trial begins with a protocol, or a plan of study. The protocol lays out the research questions of interest regarding dose, length of treatment, adverse events, potential risks and benefits and who is eligible to be recruited onto the trial. The clinical trials getting underway or being planned for COVID-19 are not “normal” in that they are “interventional” rather than purely “investigational.”  The recognition that this is a health emergency has led to bending, if not breaking, many of the clinical trials rules, especially those regarding normal “phases” through which clinical trials are conducted. 

Being enrolled in a clinical trial does not mean that you will receive the drug under investigation. Many trials include a placebo, a “fake” medication, that may look like the investigational drug. Investigators need a clear picture showing if the real drug under investigation is effective, so the investigational drug is given to one group and its effects are compared to the effects of a placebo (if any) given to a group on another “arm” of the study. Some studies, especially in Phase 3, may also use another drug for comparison to the study drug, or a combination of drugs on different arms of the study.  Some may use a placebo, or the test drug compared to the “standard” or previous treatment(s). The outcomes of a traditional clinical study are aimed at providing benefits to future patients, and not necessarily to benefit those enrolled in the study.

Trials using a placebo or combinations of drugs are generally “blinded“ so that neither the patient nor the investigators know who is getting the drug or the placebo. Once the study is completed and “unblinded,” it becomes clear what was effective and what was not. In an interventional study, investigators may still use a placebo “arm” for the study, but the beneficial results (if any) of the test drug, alone or in combination with other drugs, needs to be known as soon as possible, so an interventional clinical trial changes many things about a traditional investigational trial, especially the phases through which a study progresses and the use of other “arms” besides the investigational drug arm.

Clinical trials terminology and requirements

As mentioned earlier, a “protocol” is a plan for conducting the study in terms of which patients are eligible to be enrolled, optimal dosages of the drugs being used, including placebo, “blinding” so that patients and medical personnel don’t know who is getting which drug, and randomization of volunteers to the study’s various “arms” that may include placebo, no treatment, or other drugs. Volunteers must sign an “informed consent” spelling out the risks associated with taking an experimental drug. The consent form, as well as the study itself, must receive the OK from an Institutional Review Board (IRB) composed of physicians, scientists, other health care workers, perhaps social workers, members of the clergy and private citizens. The IRB protects the welfare of study volunteers. The US government requires an IRB and the IRB and researchers must adhere to US regulations from the Office of Human Research Protections under the Code of Federal Regulations 45,46. FDA regulations (21CFR) apply to any investigation of a drug or medical device. For a trial to move forward, the protocol and informed consent must be approved by a local IRB.

Phases 1-4

Normally, clinical trials go through a four-phase structural process. Phase 1 is carried out with a small group of people, perhaps more than 20 but fewer than 100, who are healthy volunteers. The aim is to determine an investigative drug’s safety and tolerable dose levels without incurring adverse effects.  A phase 2 study tests a larger group, perhaps from 100 to 300 volunteers, to further evaluate potential side effects and safety. In a phase 3 trial a larger group, perhaps several thousand people with the disease or condition the test drug is meant to treat, are enrolled to further evaluate the drug. A phase 3 trial will likely compare the investigational treatment against a “standard” treatment, perhaps use a placebo, or use the investigational drug in combination with other drugs. Volunteer patients are randomized to different “arms” of the study regarding which treatment they receive. These trials are usually blinded and include several “control groups” who might receive a placebo, no treatment, a combination treatment, or treatment with the investigational therapy alone. Many large Phase 3 trials will be conducted at multiple sites. The data from a Phase 3 trial will be presented to a health authority, such as the US Food and Drug Administration (FDA), or in Europe the European Medicines Agency (EMA), for approval or non-approval. A phase 4 trial is a post-marketing trial carried out after a drug is approved and has been on the market; data continues to be gathered on patients using the drug in the longer term.

The time frame for a tradition clinical trial can be from one to several years. 

Interventional clinical trials to test potential COVID-19-related drugs

In normal times, a long Phase 3 trial would be necessary for testing a new drug. But these are not normal times. Today, the disease in question and the virus that causes the disease is new, or “novel,” and many of the drugs being tested are being “repurposed” from treating other diseases. In some ways, the clinical trials process is being altered and might subsequently look more like a “crap shoot,” Vegas-style, rather than science. But these are desperate times, and time for desperate measures.

Below is a sampling of some clinical trials around the US that are either underway and recruiting volunteers, or not being conducted yet but will start recruiting soon. They all appear on www.clinicaltrials.govand have an identification number.   

Currently, the hot trials are on hydroxychloroquine (for malaria, rheumatoid arthritis and Lupus), remdesivir (for Ebola), and trials to determine if those who have survived COVID-19 have antibodies (immunity) in their blood plasma that could be made into a vaccine to help others who may get infected to survive infection, or suffer less serious symptoms.

 

Selected COVID-19 trials underway in the United States

Hydroxychloroquine for those with COVID-19 and hospitalized with symptoms

A trial recently started and recruiting volunteers is a Massachusetts General Hospital/ National Heart, Lung and Blood Institute (NHLBI) collaboration for testing hydroxychloroquine among inpatients with symptomatic COVID-19 disease. It has a identifier NCT04332991 and can be found on the www.clinicaltrials.gov  website. It is a Phase 3, multicenter, blinded, placebo-controlled, randomized trial with hospitalized adults. Patients on the drug arm will initially receive 400 mg of drug twice a day on the day of enrollment, then drop to 200 mg twice a day for the next four or five days. The point is to compare the drug to placebo outcomes at day 15 of treatment. The estimated enrollment is 510. The study started on April 2 and will run until July 2021. Contact 617-726-4777 or 617-724-9836 for the study nurses. The study is a multicenter study going on at 44 locations around the country. Participants must already be hospitalized.

 

Hydroxychloroquine to prevent symptoms in those exposed to the virus

The University of Minnesota, in collaboration with several Canadian universities, is conducting a trial to see if the study drug can prevent COVID-19 or prevent its progression in people with early symptoms.  There is a treatment arm and a placebo arm. The trial started March 17 and will run until May 12. Its clinicaltrials.gov identifier is NTC04308668. Those eligible must be over age 18 and be within their first four days of symptoms. The endpoints are symptoms after 14 days of treatment. Those with retinal eye disease, chronic kidney disease, or receiving dialysis, or those taking a number of drugs (see study on www.clinicaltrials.gov) are not eligible. Those living anywhere in the US are eligible, as are Canadians living in Quebec, Manitoba or Alberta. The study is still recruiting and expects a total of 3,000 participants. No in-person visits are necessary.

For questions email covid19@umn.edu.

 

Study to prevent COVID-19 infection in health care workers

In Texas, Baylor University is currently recruiting for a trial studying the efficacy of hydroxycholoquine in preventing infection in health care workers who are at high risk for acquiring COVID-19 from treating infected patients. Estimated enrollment is 300 participants. The study, which started on April 3 and ends July 30, is not randomized. Participants will receive 400 mg twice a day on day 1, and then receive 200 mg twice a day for seven weeks. Rate of COVID-19 conversion will be tested through nasal sampling. Outcomes will look at the first clinical worsening in seven weeks. Participants must be between 18 and 75 years of age and healthy volunteers are accepted. See ID # NCT04333225 on www.clinicaltrials.gov for exclusions. Contacts are  214-820-7224 and 214-820-7965 at the Baylor University Medical Center.

 

Selected COVID-19 trials not yet started

The University of Utah and Intermountain Health Care will be collaborating on a study comparing hydroxycholoquine alone to azithromycin alone in hospitalized patients with suspected or confirmed COVID-19.  It will be a Phase 2 study with up to 300 participants. It is scheduled to start soon and end on December 31, 2021.  The clinicaltrials.gov ID# is NCT043289832. 

The University of Pennsylvania will soon be recruiting for a clinical trial to prevent and treat COVID-19 using hydroxychloroquine (HCQ). The clinicaltrials.gov ID# is NCT04329923. There will be three cohorts. Cohort 1 will participate in a double-blind, placebo-controlled, high dose trial of HCQ as a treatment for home-bound, COVID-19 positive patients. Cohort2 will be in a randomized study using different doses of HCQ in hospitalized patients. Cohort 3 will participate in a double-blind, placebo-controlled trial of low dose HCQ as a preventive medicine for health care workers. A total of 400 participants is expected. The estimated completion date is December 1, 2021. Participants must be 18 years of age or older and healthy volunteers are accepted, but all must have access to a cell phone, tablet, or laptop computer with Internet accessibility. There will be sub-studies, each with slightly different inclusion/exclusion criteria (see www.clinicaltrials.gov for details). Contact for questions is 215-509-5690. 

Duke University (North Carolina) will be starting a clinical trial using hydroxychloroquine (HCQ) to determine its safety and validity for healthcare workers exposed to COVID-19. The clinicaltrials.gov ID is NCT4334148. It will be a double blind, placebo-controlled study of up to 15,000 health care workers at risk for COVID-19 exposure. There will be a baseline assessment using nasal swabs and a blood sample. The course of treatment will be 30 days with self-administered tablets of either HCQ or placebo with final nasal swabs and blood tests at the trials end. Eight weeks after the trial starts there will be a final contact between trial participants and those conducting the trial. Outcomes include adverse events and positive testing for COVID-19. Work exposures, such as in ICU, emergency departments, or respiratory services are required. Exclusion is for previous COVID-19 diagnosis. Contacts are 919-668-5590 and 919-668-4084.

Other efforts

A treatment that may be more effective than a drug (if it works) would be creating a vaccine using the blood plasma of those who have contracted COVID-19 and, having survived, have antibodies (immunity) so that when their blood plasma is injected into healthy persons, the antibodies act as a deterrent to infection or help to reduce the severity of symptoms. 

Some experts suggest that COVID-19 might be around for some time, or perhaps even become seasonal, as influenza is. To have this method work well the antibodies would have to be “durable” and not disappear quickly from those who have survived infection. Should the antibodies not be durable, some experts also hope that those who have had infections may not get another infection if their immune system’s T-cells (called “killer” T cells) can have the “memory,” and perhaps the “muscle,” to fight off new infections if the antibodies from prior infections don’t endure.

Final notes

In an April 5 statement, the American Association of Pharmaceutical Scientists (AAPS) said that “pharmaceutical-research experts are raising concerns that attempts to offer desperate coronavirus patients some form of treatment may hobble crucial studies of which drugs actually work and which ones don’t.”

While these are not normal times for us or for the conduct of the clinical trials process, even as you read this, clinical trials for new drugs to fight cancer and other serious diseases may be grinding to a halt. Many, if not most, clinical trials are conducted on an “out-patient” basis where participants report physically to a trial site to be clinically evaluated for what their trial drug may or may not be doing for them, or to them. Comprehensive physical examinations and blood draws are important. Too important to miss. With social/physical distancing, in-person examination is difficult and telemedicine via Internet has limits in terms of examination. Thus, the hopes for surviving a serious disease by getting experimental drugs through a clinical trial may be now a fleeting experience, and for some time. And many drugs in the evaluation “pipeline” for future patients may not be able to proceed.

Finally, one knows these are not normal times because of the efforts to repurpose drugs to fit another disease, and do so with only a glimmer of hope. Also, one should know these are not normal times when political leaders, especially those political leaders who may have conflicts of interest with the test drugs, have enough power to preempt and bully scientists. The MDs and PhDs who conduct studies are required to have no conflicts of interest with the drugs they test. Further, they are responsible to IRBs, responsible for complying with approved practices and, foremost, responsible to – and for – their patients. Clinical trials principal investigators should not be held hostage by elected officials who have inflated egos but no clinical background or scientific training.

EDITOR'S NOTE:

Randolph Fillmore, MA, MA is a science and medical writer, a former respiratory therapist and a former clinical trials coordinator.

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