ALS Clinical Trials 101
What is a Clinical Trial?
A clinical trial is a type of research study using human volunteers (also called participants). The purpose of these studies is to add to current medical knowledge by evaluating the safety and usefulness of new treatments. Types of treatments investigated by the clinical trial may include drugs, devices, or procedures. Clinical trials are the best way to find effective therapies while weeding out treatments that may be useless or harmful.
In a clinical trial, participants receive specific treatments according to the research plan (called a protocol). These treatments have some differences from typical medical treatments prescribed by doctors. Clinical trials intend to answer specific questions about the therapy itself by studying the treatment in many volunteers. Because of this, clinical trials require that the treatments follow precise timelines given in the research protocol. The treatments in clinical trials are not considered to have “proven” benefit to patients, and clinical trials using these treatments are generally intended to benefit future patients.
In contrast to a clinical trial, typical medical treatment provided by your doctor is intended to treat you individually. Your doctor makes real-time decisions about your treatment needs using products and procedures that are already considered safe and effective by medical professionals. While your safety is of the utmost importance in a clinical trial, the research protocol must generally be followed as closely as possible. Doing so allows researchers to compare your results to the results from the other participants in the trial.
Clinical trials are conducted in phases to ensure the safety of the participants. There are 4 phases of clinical trials, and a drug, device, or procedure being tested in a trial can potentially fail at any one of the phases. At each phase, the product or procedure under investigation is used to treat more participants, and the requirements for the treatment to move on to the next phase change.
Phase one evaluates the safety and dosage of the treatment. Typically, this involves the participation of around 20-100 healthy volunteers or people with the target condition. This phase ensures that the drug or procedure will not harm the participants in the study. In drug studies, the dosage of the medication during this phase is often slowly increased to show that the drug does not cause any problems at a low dose before moving to a higher dose. Approximately 70% of medicines that go through Phase One move on to Phase Two.
Phase Two investigates the efficacy and side effects of the drug. During this phase, researchers try to determine if the drug has the potential to work as a treatment for the indicated disease. Up to several hundred people with the target condition are included in Phase Two studies, and their symptoms are monitored to look for improvement or stability. Also, researchers will look for any unanticipated responses to the drug, also known as side-effects. Approximately 33% of therapeutic agents that go through Phase Two move to Phase Three.
In Phase Three, a more extensive study is conducted to review the efficacy of the treatment and monitor any adverse reactions. Phase three of a study typically includes Around 300-3,000 people with the target condition, and they are observed for any positive or negative outcomes from the treatment. Approximately 25-30% of drugs move to the next phase.
Phase four evaluates the long-term safety and efficacy of the treatment. By this time, the therapy may already have received approval for use in the general population and is generally accepted as effective. However, the long-term effects of the treatment must still be monitored.
In clinical trials, the experimental treatment often is compared to a placebo. The placebo is an inactive treatment that looks like the experimental treatment but has no effect. In drug studies, the placebo is sometimes referred to as a “sugar pill.”
It is important to remember that the experimental treatments in clinical trials are new and unproven—that is why they need to be tested! Experimental treatments may have a positive effect, no effect, or even an adverse effect. For researchers to be sure that any results they see are due to the treatment itself and not some other factor, it is essential to compare the experimental regimens to placebo.
The Placebo Effect
The use of placebos reduces the chance that any positive benefit seen from the experimental treatment is due to the placebo effect. The placebo effect occurs when a placebo improves the patient’s condition only because the person believes it will be helpful. The placebo effect can be potent, and the strength of the effect is increased by the intensity of the treatment. So, an experimental treatment that did not have any benefit on a patient’s disease could still make the patient feel better just because the patient believed that the treatment would help. By comparing active treatment to a placebo in a clinical trial, researchers can get an answer to whether the active treatment is helpful relatively quickly and without doubts about the actual effectiveness of the therapy.
In ALS specifically, placebos are essential because of the diversity of people with ALS. ALS can present itself very differently from one individual to another. For example, some people with ALS have a rapid progression of the disease, while for others progression is relatively slow. Using a placebo in clinical trials increases the chance that any benefit seen from the active treatment will be real effects of the treatment, rather than individual differences in patients in each group.
Participants in a placebo-controlled trial are randomly assigned to one of two groups. One group will receive active treatment, while the second group will receive a placebo treatment. It is crucial that no one from either group can tell which group they are in so that everyone will have the same beliefs about the treatment. Everything is conducted the same way for both groups in the study. This way, researchers can control for the placebo effect.
Individuals are assigned to the treatment or placebo groups using a process called randomization. Typically during randomization, a specialized, study-specific computer program will assign you to either placebo or the active study treatment. Usually, when a study is comparing active treatment to a placebo, the computer will be programmed to give you a 50/50 chance of being in the active treatment group. This is similar to flipping a coin—there is a 50% chance it will land on heads.
In a double-blind trial, neither the participants nor the researchers know who is getting active treatment and who is getting a placebo. When the researchers do not know who is getting which type of therapy, they cannot treat the two groups any differently. This is the gold standard for clinical trials and ensures that any biases that the researchers may have about the treatment cannot affect the trial. At the end of the trial, the researchers can break a code that tells them who received each type of treatment to analyze the data.
Joining a research study is a big decision that could have lasting effects on your health. You should carefully consider why you want to join a trial and any consequences of entering the trial. During your decision period, you should feel free to ask as many questions about the study as you want. Some questions you may want to ask include:
- What is the purpose of the study?
- Who is going to be in the study?
- Why do researchers believe the experimental treatment may be useful?
- Has this treatment been tested before?
- What are the chances of getting the placebo?
- What kinds of tests and experimental treatments are involved?
- How do the possible risks, side effects, and benefits in the study compare with my current treatment?
- How long will the trial last?
- Who will pay for the experimental treatment?
- Will I be reimbursed for other expenses?
- What type of long-term follow-up care is part of the study?
Your Study Team
If you decide to participate in a clinical trial, you will have a team of individuals that will assist you through the trial. These will include:
- The Site Principal Investigator (PI): This is the primary doctor responsible for the overall conduct of the study at your study site. In ALS studies, this is usually a neurologist specializing in ALS.
- Study Coordinators: The coordinator(s) will be your primary contact and source of information for all things related to the study. There may be one dedicated coordinator for the study, or there may be multiple different coordinators who help with a given study. The study coordinator may or may not be a registered nurse, but they are on the research protocol. The study coordinator will typically be the one who performs study visits and procedures, although sometimes a medical doctor will be asked to assist with specific procedures.
- You: You are your biggest advocate in a study. If you are entering a drug study, you may need to take the medications at the prescribed time(s) each day. You are responsible for letting the coordinator or PI know if you notice any changes or have any issues during the study. When you agree to be a part of the study, you agree to do your best to follow the study protocol so that your data will be useful to the researchers conducting the investigation.
Step One: The Screening Visit
To participate in a clinical trial, you must first schedule a screening visit. During the screening visit, the study team will first go through an informed consent procedure with you. The informed consent procedure is intended to give you a detailed review of the study, including who is conducting the research, the purpose of the study, what is involved in the study, known risks associated with the study, and your rights and responsibilities as a study participant. This includes an informed consent form that gives you all of the information that you need to know about the study to make a knowledgeable decision about whether to participate. Questions are highly encouraged during this time as they can help you feel comfortable with the answers. You want to understand the trial and your involvement in it. Once you fully understand the nature of the research and decide to move forward, you will sign the informed consent. You will get a copy of this informed consent for your records.
After the informed consent process is complete, the study staff will review your eligibility for the study. This helps to ensure that you are a good fit for the study and that you meet the inclusion and exclusion eligibility criteria listed in the study protocol. In an ALS study, common procedures during this portion include:
- A detailed review of your history of ALS onset and diagnosis
- A comprehensive review of your medical history
- A detailed medication review
- Blood work and ECG
- Answering a questionnaire about your daily function
- Baseline assessments of respiratory status and muscle strength, and
- A physical and neurological exam
Step Two: The Baseline Visit
Once you have completed the screening visit and the study staff has confirmed your eligibility, you will be scheduled for a baseline visit. This visit sets the starting point for the study, and all other measurements taken during the study will be compared to your baseline measurements. During this visit, the study staff will often review your medical history and medications for any changes since your last visit and may repeat some of the assessments from the screening visit.
Randomization usually occurs during the baseline visit. The study staff will use a study-specific computer program to receive your study assignment to either placebo or active treatment. However, the study staff will usually not know which treatment you have been assigned to—they are only given a code to tell them which kit number you have been assigned to. The kits have been pre-assembled by the study sponsor so that the study staff at your site do not know which treatment is in which kit.
After randomization, participants normally receive the first dose of the treatment. You will also likely receive a take-home supply of the study drug, a study drug diary to record when you take the medication and a visit schedule for your upcoming appointments.
Subsequent Study Visits
After your baseline visit, you will be asked to come back to the clinic for regularly scheduled appointments. These subsequent visits are required by the study protocol and must be within a specific time frame. During these visits, you will be asked about any side effects, adverse reactions, or other changes in your health. You may also be asked to repeat some of the study assessments or procedures as required by the study plan. At these visits, you will also be asked to bring back any unused study drug, and you may receive a new supply.
End of Study Visit/Follow-up Visit
Once you have completed the treatment regimen per the protocol, you will have a final study visit. During this visit, you will turn in any leftover drug, repeat any study assessments required by the protocol, and provide information on any side effects or changes in your health. You have completed the clinical trial!
Possible Open-Label Extension Study
Some studies may offer you the opportunity to continue in an “open-label” phase after the trial. During this phase of the trial, you are given active study treatment (there are no placebos during this phase), so both you and the study staff know you are receiving the drug. Study procedures for Open-Label Extensions vary but are usually similar to the previous study.
The data from the study are analyzed after the study. The results from the study will be made public, and you should be notified of the results as well as what group you were assigned to (active study treatment or placebo). However, analyzing data from a clinical trial can take many months, and you may have to wait at least 3-6 months to receive the results.
Sometimes, clinical trials come back with negative results. This could mean that the study treatment had no effect compared to placebo, or it had an adverse effect. While negative results are disappointing, they still provide valuable information. Negative results can strengthen future studies by telling us where to stop looking, or where to look further. They also save patients from dangerous or useless treatments.
While clinical trials are essential to find and test new treatments, there are different types of research studies that do not involve experimental therapies. Some studies are created to learn more about ALS as a disease—these may include observational studies and biomarker studies.
Observational studies do not attempt to treat ALS. Instead, they try to learn more about who is affected by ALS, how ALS progresses, and what might be critical indicators of the disease. Participants in these sorts of studies do not get any experimental drugs or treatments, but they may be asked to come into the clinic at various time points to answer questions and have measures taken. Researchers can analyze the responses and measurements from these visits to learn about how the disease works. By increasing knowledge about the disease, researchers may find new avenues of treatment to explore.
Biomarker studies are an essential part of ALS research that have traditionally been neglected. However, researchers now realize the importance of biomarkers in ALS, and more studies are incorporating biomarkers. Biomarkers are anything that can be measured to provide information about the disease subtype, progression cause, or response to treatment. Examples of biomarkers include blood, spinal fluid, questionnaire scores, breathing tests, and genetic tests.
Biomarkers may be the key to finding effective treatments for ALS. Currently, ALS is thought of as one single disease with lots of different presentations. This means that no two individuals with ALS are the same. Some individuals with ALS might progress quickly or slowly. The disease may start in the face, the hands, or the feet. The disease duration can be quite long or extremely short. These different presentations of the disease give us a clue that perhaps there are different subtypes of ALS, and the different subtypes might respond to different types of treatment. However, to figure out if there are different subtypes of the disease, and which treatments work best with which subtypes, researchers first need to understand how to distinguish the different subtypes. This will be done using biomarkers.
To find biomarkers that provide useful information about ALS, researchers need to perform biomarker studies to collect large quantities of the biomarker. For example, if a particular (currently unknown) biomarker can show us a subtype of ALS that affects 10% of individuals with ALS, then to discover this biomarker researchers will need to study dozens of individuals. By collecting data on 20 individuals, researchers would only have (on average) two individuals whose biomarker shows the ALS subtype. This may not be enough to distinguish the subtype due to individual variation. Thus, researchers need to collect data and biofluids (such as blood or spinal fluid) from hundreds of people to look for useful biomarkers.
Biomarker studies may be a one-time visit where researchers collect data or biofluids, or they can include several visits over a more extended period. Some biomarker studies can be after death through tissue donation. As data and samples are collected, they are “banked” into biorepositories. These storehouses hold data from hundreds of patients so that researchers can request access to the data to do more specific research to find similarities in the data or samples. By increasing and improving the available biomarkers, drug studies may become faster and easier because the drugs could be tested on specific subtypes of ALS. Biomarker research has the potential to change the trajectory of ALS research forever.
If you are interested in participating in research, discuss any available opportunities with your neurologist. Here at the Gregory W. Fulton ALS Center at Barrow Neurological Institute, we have many opportunities for research participation, including clinical trials, biomarker studies, and tissue donation. You can also find more information about current clinical trials at the websites below.