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Clinical Trials

Clinical research is simply medical research involving people. Here we explore clinical trials and the basics of what you need to know, and how clinicians are working to improve racial and ethnic representation in amyloidosis clinical trials.

 

WHAT ARE CLINICAL TRIALS?

According to the National Institutes of Health (NIH), clinical trials are research studies performed on people that are aimed at evaluating a medical, surgical, or behavioral intervention. Clinical trials are the primary way that researchers find out if a new treatment, like a new drug or medical device (e.g., a pacemaker) is safe and effective in people. Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment. Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still, others test ways to prevent a health problem before it begins. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem.

 

WHY CLINICAL TRIALS ARE IMPORTANT

Clinical trials permit researchers to test the safety and effectiveness of new therapies. They also allow for a rigorous evaluation through patient participation. Bottom line: it is only after the extensive evaluation and testing from a clinical trial that the FDA will approve the widespread use of any new therapy.

 

WHAT ARE THE PHASES OF CLINICAL TRIALS?

All clinical trials must be approved by the U.S. Food and Drug Administration (FDA) before they can begin. Prior to that decision, scientists perform laboratory tests and studies in animals to test a potential therapy’s safety and efficacy. Assuming favorable outcomes, the FDA then gives approval for a clinical trial involving humans.

Clinical trials are comprised of four phases to test a treatment, find appropriate dosages, and detect side effects. If following the completion of the first three phases, researchers find the drug or intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its effects. Overall, the duration of a clinical trial spans years.

 

WHY PEOPLE CHOOSE TO JOIN A CLINICAL TRIAL

There are many reasons why people choose to join a clinical trial. Some join a trial because the treatments they have tried for their health problem did not work. Others participate because there is no treatment for their health problem. Some studies are designed for, or include, people who are healthy but want to help find ways to prevent a disease that may be common in their family. By being part of a clinical trial, participants may access new treatments before they are widely available. Especially with a rare disease such as amyloidosis, clinical trials may offer a meaningful impact to a patient’s quality of life.

In addition, people may feel that participating in a clinical trial allows them to play a more active role in their own health care. Participants may receive more frequent health check-ups and closer monitoring through the clinical trial. Other people say they want to help researchers learn more about certain health problems. Whatever the motivation, when choosing to participate in a clinical trial, one becomes a partner in scientific discovery. This can also help future generations lead healthier lives. Major medical breakthroughs could not happen without the generosity of clinical trial participants—young and old.

 

POTENTIAL RISKS OF A CLINICAL TRIAL

There are no guarantees of success from a clinical trial, and there are risks. For starters, there may be serious side effects. Also, the therapy may not improve upon current treatment, or may not even work at all. Finally, as a clinical trial participant, you may be part of the control group, which means either standard treatment or no-treatment placebo. In other words, there are no assurances you would receive the new therapy.

 

FINDING A CLINICAL TRIAL

Thanks to the internet, folks can find lots of information regarding the wide array of open clinical trials. So much so that it may be overwhelming. Particularly with regards to amyloidosis, casting such a wide net may not be the most productive. Since finding an appropriate clinical trial is not easy for such a rare disease, here are a few excellent places to start.

  • My Amyloidosis Pathfinder (MAP). Developed by the Amyloidosis Research Consortium (ARC), MAP helps patients discover and learn about amyloidosis-related clinical trials. After answering a short questionnaire, MAP matches patients to trials specific to their condition and ones for which they may be eligible.
  • Amyloidosis Treatment Centers. The list of amyloidosis centers participating in clinical trials in the U.S. is growing. Below we list three active participating centers.
  • ClinicalTrials.gov. This resource, provided by the U.S. National Library of Medicine, is a database of over 250,000 privately and publicly funded clinical studies conducted around the world (in all 50 states in the U.S. and 204 countries).

 

DECIDING WHO PARTICIPATES IN CLINICAL TRIALS

After signing the informed consent form, the clinical staff will screen the candidate against the clinical trial criteria. The screening may involve cognitive and physical tests. Inclusion criteria for a trial might include age, stage of disease, gender, genetic profile, family history, and whether or not the candidate has a study partner who can accompany them to future visits. Exclusion criteria might include factors such as specific health conditions or medications that could interfere with the treatment being tested. Generally, individuals can participate in only one trial or study at a time. Different trials have different criteria, so being excluded from one trial does not necessarily mean exclusion from another.

In the following video, Dr. Frederick Ruberg, cardiologist at the Boston University Amyloidosis Center, discusses the diversity of racial and ethnic occurrences of amyloidosis, and why this should parallel patient representation in clinical trials. He illustrates the persistent disparities observed by race and ethnicity and how un-recognized ATTR amyloidosis, for example, could be contributing to such differences. Adding more evidence, he shares how published clinical trials of ATTR-CM agents are insufficiently diverse. He summarizes possible solutions for improving future clinical trial participation.

 

Clinical trials need numbers and diversity of patients that reflect the patient community.  Many volunteers must be screened to find enough people for a study, and with rare diseases such as amyloidosis, important trials are often significantly delayed due to a lack of participants. This can seriously slow down the rate at which new drugs are discovered, tested, and made available to patients.

 

CONCLUSION

Not all clinical trials have successful outcomes. However, every disease drug and therapy treatment prescribed today is the result of clinical research. Clinical trials are absolutely necessary to determine that a treatment is safe and that it has a real positive effect on a particular disease, better than that observed by a placebo or the current standard of care. In addition, ensuring participant diversification adequately reflects the patient population is an important consideration when recruiting for clinical trials. Clinical trials are how we will learn more about amyloidosis, discover new drugs and treatment therapies, and find a cure.

Additional information regarding clinical trials, including where to find clinical trials and participant protection and safety, can be found in Clinical Trials 101.

 

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SOURCES

Amyloidosis Research Consortium

Boston University / Boston Medical Center, Amyloidosis Center

The Clinical Study Center

Mayo Clinic

National Institute on Aging

National Institutes of Health

Stanford University Amyloid Center

U.S. National Library of Medicine

 

CRISPR/Cas9 – ATTR Clinical Trial Update

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.” In this piece we provide a clinical trial update for transthyretin (TTR) amyloidosis using this technology.

 

CRISPR FIXES GENES INSIDE THE BODY (3)

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.”

CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings.

 

APPLYING THE CRISPR TECHNOLOGY (3)

Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat.The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.”

Facts about Transthyretin (ATTR) Amyloidosis. Source: https://ir.intelliatx.com/

 

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

Intellia Therapeutics and Regeneron shared a press release recently announcing initial data from the cardiomyopathy arm of the ongoing Phase 1 trial of NTLA-2001, an investigational single-dose in vivo CRISPR-Cas9 therapy for the treatment of transthyretin (ATTR) amyloidosis.

According to that press release, the interim data include 12 adult patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) with New York Heart Association (NYHA) Class I – III heart failure. Single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001 were administered intravenously, and the change from baseline in serum transthyretin (TTR) protein concentration was measured for each patient. The data revealed that treatment with NTLA-2001 led to rapid and deep reductions of up to 94 % in serum TTR by day 28. In February 2022, the companies reported clinical data that revealed rapid, deep and sustained responses in a cohort of 15 patients with hereditary transthyretin (TTR) amyloidosis with polyneuropathy (ATTRv-PN).

ATTR is a rare, progressive disease, in which a protein known as TTR becomes misfolded and accumulates as plaques in tissues throughout the body. This causes serious complications that mainly involve the heart and nerves, and most patients die 2-15 years after disease onset. NTLA-2001 was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to treat ATTR by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-based inactivation of the TTRgene in liver cells.

Read more about the available clinical data for NTLA-2001 in a previous CMN clinical trial update here.

BACKGROUND

Back in May, 2021 we wrote about the breakthrough gene-editing technology CRISPR being applied to hereditary transthyretin amyloidosis (hATTR), worthy of a background read for those unfamiliar with this science or those looking for a refresher.

BLOG – CRISPR/Cas9 – Editing the Code of Life

 

 

Sources:

  1. CRISPR Medicine News: Special Update: News from the Gene-Editing Clinical Trials
  2. CRISPR Medicine News: CRISPR Therapy for Transthyretin Amyloidosis Results in Rapid and Prolonged Responses
  3. NIH Director’s Blog
  4. BLOG – CRISPR/Cas9 – Editing the Code of Life

FDA Drug Approval Process

Drugs are the lifeblood of patient treatments, and the development of new drugs is critical. Overseen by the FDA (U.S. Food and Drug Administration), they define a drug as “any product that is intended for use in the diagnosis, cure mitigation, treatment, or prevention of disease; and that is intended to affect the structure or any function of the body.”

The FDA’s Center for Drug Evaluation and Research (CDER): “The center’s evaluation not only prevents quackery, but also provides doctors and patients the information they need to use medicines wisely. CDER ensures that drugs, both brand-name and generic, are effective and their health benefits outweigh their known risks.”

There are several phases (comprising twelve steps) of the FDA drug development and approval process, depicted in a two-page graphic here, and described below.



PRE-CLINICAL RESEARCH

This is the drug sponsor’s discovery and screening phase, comprising two steps.

The Start. The sponsor develops a new drug compound and seeks to have it approved by the FDA for sale in the U.S.

Step 1: Animals Tested. The sponsor must test the new drug on animals for toxicity. Multiple species are used to gather basic information on the safety and efficacy of the compound being investigated/researched.

Step 2: IND Application. The sponsor submits an Investigational New Drug (IND) application to the FDA based on the results from initial testing that includes the drug’s composition and manufacturing, and develops a plan for testing the drug on humans (aka a clinical trial).

The FDA reviews the IND to assure that the proposed studies, generally referred to as clinical trials, do not place human subjects at unreasonable risk of harm. The FDA also verifies that there are adequate informed consent and human subject protection.

 

CLINICAL

This phase is all about the clinical trial, all of which must be approved by the FDA before they can begin. In an earlier blog – Clinical Trials 101 – we offer an expanded discussion along multiple facets regarding clinical trials which you may find informative.

According to the National Institutes of Health (NIH), clinical trials are research studies performed on people that are aimed at evaluating a medical, surgical, or behavioral intervention. Clinical trials are the primary way that researchers find out if a new treatment, like a new drug or medical device (e.g., a pacemaker) is safe and effective in people. Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment. Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still, others test ways to prevent a health problem before it begins. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem.

Clinical trials are comprised of four phases to test a treatment, find appropriate dosages, and detect side effects. If following the completion of the first three phases, researchers find the drug or intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its effects. The fourth phase continues post-FDA approval. Overall, the duration of a clinical trial spans years.

Step 3: Phase I Trial. A Phase I trial tests an experimental treatment on a small group of often healthy people (20 to 80 in number) to judge its safety and side effects and to find the correct drug dosage.

Step 4: Phase 2 Trial. A Phase II trial uses more people (100 to 300 in number). While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. These trials also continue to study safety, including short-term side effects. This phase can last several years.

Step 5: Phase 3 Trial. A Phase III trial gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people. If the FDA agrees that the trial results are positive, it will approve the experimental drug or device.

 

NDA (NEW DRUG APPLICATION) REVIEW

This phase covers the FDA’s New Drug Application (NDA) review.

Step 6: Review Meeting. The FDA meets with the sponsor prior to submission of the NDA.

Step 7: NDA Application. The sponsor formally asks the FDA to approve a drug for marketing in the United States by submitting an NDA. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured.

Steps 8-9: Application Reviewed. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. If the FDA files the NDA, the FDA Review Team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.

Step 10: Drug Labeling. The FDA reviews the drug’s professional labeling and assures appropriate information is communicated to health care professionals and consumers.

Step 11: Facility Inspection. The FDA inspects the facilities where the drug will be manufactured. 

Step 12: Drug Approval. The FDA reviews will approve the application or issue a response letter.

 

POST-MARKETING RISK ASSESSMENTS

Phase IV clinical trial for drugs or devices takes place after the FDA approves their use. A device or drug’s effectiveness and safety are monitored in large, diverse populations, where the sponsor is required to submit periodic safety updates to the FDA. Sometimes, the side effects of a drug may not become clear until more people have taken it over a longer period of time.

 

WHO REVIEWS NEW DRUG SUBMISSIONS?

A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists review the drug sponsor’s data and proposed labeling of drugs.

 

WHAT OTHER DRUG PRODUCTS ARE REGULATED BY THE FDA?

Drugs include more than just medicines. For example, fluoride toothpastes, antiperspirants (not deodorant), dandruff shampoos, and sunscreens are all considered drugs.

 

CONCLUSION

FDA approval of a drug means that data on the drug’s effects have been reviewed by CDER, and the drug is determined to provide benefits that outweigh its known and potential risks for the intended population.

 

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SOURCE

National Institutes of Health

U.S. Food and Drug Administration

Drugs.com



CRISPR/Cas9 – Editing the Code of Life

AN UPDATE  …..  WOO HOO!!!

Well, the results of the preclinical studies were presented on June 26, 2021 and it is fantastic news for hereditary ATTR amyloidosis patients!!!

Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram.

CONCLUSIONS
In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.)

The New England Journal of Medicine
https://www.nejm.org/doi/full/10.1056/NEJMoa2107454

Our original blog post ….

 

The scientific world is abuzz … a Nobel Prize-winning technology called CRISPR/Cas9 can now edit our DNA. This programmable gene-editing technology, which is efficient, precise, and scalable, has inspired a gold rush of countless applications in medicine, agriculture and basic science. Early areas of focus include genetic diseases such as sickle cell and hereditary ATTR amyloidosis, offering new and exciting optimism.

Ground-Breaking Science in Gene Editing

“A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome – more than three billion DNA base pairs – is contained in all cells that have a nucleus.”  – Intellia Therapeutics

CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, is a microbial ‘immune system’ that prokaryotes — bacteria and archaea — use to prevent infection by viruses called phages. At its core, the CRISPR system gives prokaryotes the ability to recognize precise genetic sequences that match a phage or other invaders and target these sequences for destruction using specialized enzymes.

Previous work had identified these enzymes, known as CRISPR-associated proteins (Cas), including one called Cas9. But scientist Emmanuelle Charpentier, working first at the University of Vienna and later at the Umeå Centre for Microbial Research in Sweden, identified another key component of the CRISPR system, an RNA molecule that is involved in recognizing phage sequences, in the bacterium Streptococcus pyogenes, which can cause disease in humans.

Charpentier reported the discovery in 2011 and that year struck up a collaboration with American biochemist Jennifer Doudna. In a landmark 2012 paper in Science, the duo isolated the components of the CRISPR–Cas9 system, adapted them to function in the test tube and showed that the system could be programmed to cut specific sites in isolated DNA – an incredibly precise set of DNA-editing genetic scissors. In 2020, Doudna and Charpentier won the 2020 Nobel Prize in Chemistry for their gene-editing technology.

“The ability to cut DNA where you want has revolutionized the life sciences,” said Pernilla Wittung Stafshede, a biophysical chemist and member of the Nobel chemistry committee, at the prize announcement. “The ‘genetic scissors’ were discovered just eight years ago, but have already benefitted humankind greatly.”

 

How Does CRISPR/Cas9 Work? (3)

This technology acts as an incredibly precise set of molecular scissors, providing instructions to cut an identified gene in a specific position in the nucleus of DNA. There are two primary components to the CRISPR/Cas9 genome editing system:

  • The Cas9 protein, which initially recognizes the DNA and also acts like a pair of “molecular scissors” that precisely cleaves the targeted DNA sequence.
  • The guide RNA, which guides the Cas9 scissors to the desired target DNA sequence and activates the scissors so they cut.

https://www.intelliatx.com/crisprcas9/how-crisprcas9-works/

Background on Hereditary Transthyretin Amyloidosis (hATTR/ATTRv) (1)

Transthyretin amyloidosis is a slowly progressive condition characterized by the buildup of abnormal deposits of a protein called amyloid (amyloidosis) in the body’s organs and tissues. These protein deposits most frequently occur in the peripheral nervous system, which is made up of nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves result in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis. In some cases, the brain and spinal cord (central nervous system) are affected. Other areas of amyloidosis include the heart, kidneys, eyes, and gastrointestinal tract. The age at which symptoms begin to develop varies widely among individuals with this condition, and is typically between ages 20 and 70.

There are three major forms of transthyretin amyloidosis, which are distinguished by their symptoms and the body systems they affect.

  1. The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions.
  2. The leptomeningeal form of transthyretin amyloidosis primarily affects the central nervous system.
  3. The cardiac form of transthyretin amyloidosis affects the heart.

Mutations in the TTR gene causes the liver to product the TTR protein in a misfolded form. This misfolded protein can then build up in the body and lead to disease-causing nerve and other organ damage.

 

Clinical Trial Research (4)

According to CRISPRMedicineNews, one of the early clinical trials within gene editing is focused on hereditary transthyretin amyloidosis. In these trials, CRISPR-Cas is either used directly to treat the condition by editing an individual’s genome in vivo or indirectly through ex vivo engineering of a cell-based therapy. An update published November 17, 2020 discusses the clinical trial, which is now underway in the U.K.

CRISPR-Cas9 Trial For NTLA-2001 to Treat Hereditary Transthyretin Amyloidosis With Polyneuropathy

The second newly-added trial is sponsored by US-based Intellia Therapeutics and seeks to enroll 38 participants who are diagnosed with polyneuropathy (PN) due to transthyretin (TTR) amyloidosis (ATTR).

This open-label Phase 1 two-part trial comprises a dose escalation followed by a safety dose expansion study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of Intellia’s most advanced in vivo CRISPR-based therapy candidate, NTLA-2001.

ATTR is a hereditary progressive condition that is characterized by an accumulation of misfolded transthyretin (TTR) protein. The disease results from mutation(s) in the TTR gene, leading to mutant TRR protein that is unstable and easily forms aggregates that deposit as amyloid in various organs and tissues in the body. Organs or body parts most often affected include the nerves, heart, kidneys and eyes.

Life expectancy is typically 2-15 years from disease onset, and current treatment options include transplantation of affected organs and medications to slow progression of disease symptoms.

NTLA-2001 is the first investigative CRISPR-based therapy to be administered in vivo in humans. The new therapy comprises TTR-targeting gRNA and Cas9 mRNA, both of which are delivered in vivo via Intellia’s proprietary lipid nanoparticle technology. Pre-clinical studies support the notion that NTLA-2001 has potential as a one-time curative treatment. The first patient was dosed with NTLA-2001 last week and the study is expected to be completed in 2024.

Worldwide prevalence of spontaneous and hereditary transthyretin amyloidosis (ATTR). Source: Intellia Therapeutics. https://www.intelliatx.com/in-vivo-therapies/

 

Potential Game-Changer for Hereditary ATTR Amyloidosis

 “Once we’ve assessed safety and established an optimal dose, we intend to rapidly initiate trials for the clinical manifestations of ATTR. NTLA-2001 may halt and reverse ATTR progression by producing a deeper, permanent TTR protein reduction for all patients – regardless of disease type – than the chronically administered treatments currently available.” said Intellia Therapeutics President and CEO, John Leonard, M.D.

 Intellia’s proprietary CRISPR/Cas9 system could potentially address diseases with a single course of treatment because it permanently repairs the defective DNA. This represents a breakthrough improvement over current therapies, most of which require lifelong administration because they cannot correct underlying causes of the disease. However, this technology does not pass the genetic changes made to the patient to his or her offspring … the “fix” will not pass from generation to generation.

 

This is exciting news, giving new hope for families who have been ravaged by disease over generations.

 

 

 

 

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If you’d like to read more about Jennifer Doudna, here’s a book recently released by bestselling author Walter Isaacson, The Code Breaker.

 

Sources:

  1. https://crisprmedicinenews.com/clinical-trial/transthyretin-amyloidosis-attr-nct04601051/
  2. crisprmedicinenews.com
  3. https://www.intelliatx.com
  4. https://crisprmedicinenews.com/news/crispr-cas-clinical-trial-update/
  5. https://www.nature.com/articles/d41586-020-02765-9
  6. Doudna Lab, Berkeley, California
  7. CRISPR Therapeutics, Cambridge, Massachusetts
  8. Innovative Genomics Institute, Berkeley, California

 

Amyloidosis By The Numbers

 

As a member of the amyloidosis community, we consistently engage in conversations with patients across a variety of forums. One constant among these patients is a desire for more knowledge. We want to learn about symptoms, treatments, and how we are all impacted by this disease. To get some answers, Mackenzie’s Mission created a series of online questions. We heard from 575 respondents. Here are their answers.  Disclaimer: we are simply reporting the data as submitted.

 

In response to what is your current age today, the range was between 20 and 89, with 92.6% falling between the age of 40 and 79, and 83% falling between the age of 50 and 79.

 

 

In response to what was your age at time of diagnosis, the range was between 10 and 89, with 91% falling between the age of 40 and 79, and 63.8% falling between the age of 50 and 69.

 

 

The gender of respondents was somewhat balanced, with 54.5% female and 45.5% male.

 

 

The respondents currently live in 25 countries/areas around the globe, with 82.09% from the United States.

 

 

The types of amyloidosis were also diverse, including Primary/AL, hATTR, ATTRwt, Localized, and Secondary/AA.  About 3% of the respondents were types outside of these, or unknown.

 

When asked about the number of organs affected, the majority at 56.5% had two or more, followed by 36.7% with one organ involved. A small 6.8% had no organ involvement.

 

Next, we asked the respondents for specifics as to which organs had been affected by the disease. The heart and kidney were the most common, with the GI Tract and Nervous System coming in similarly at third and fourth. Fewer respondents listed problems with the liver, lungs, spleen and larynx. In addition, there was a surprisingly long list of other involvements filled in, each receiving just one tally.

 

The next four questions focused on the specialty of doctors that patients had visited, and the time to diagnosis.  We first asked how many doctors each respondent saw before getting a diagnosis. It is interesting to see how evenly it is spread across the selections.

 

We then wanted to know where their journey began. What was the specialty of the first doctor the respondent visited?  It was not a surprise that the majority of responses, at 53.9%, named their PCP/Internal Medicine as their first stop.

 

The next question was to determine what type of doctor made the amyloidosis diagnosis. The data seems to indicate that while PCP/Internal Medicine was the first point of inquiry at 53.9%, they arrived at a diagnosis only 1.9% of the time. Thus, referrals to specialists were key to getting a diagnosis, with nephrologists, hematologists/oncologists, and cardiologists the front runners at an aggregate of 72.9%. Having said that, per the earlier chart, it took many specialists to arrive at the answer.

 

Next, we wanted to know how long it took to get a diagnosis. We were surprised to learn that 50% of respondents said they received a diagnosis within the first six months, especially given the number of doctors visited to arrive at the diagnosis.

 

We then asked respondents to list all symptoms they experienced. The dominant symptoms were fatigue and shortness of breath – 64.2% and 53.7% respectively. The “Other” category came in strong at 22.4%, with an extremely long and diverse list of additional symptoms (too many to mention here). It does seem appropriate to observe that the diversity of symptoms reflects the complexity of this disease.

 

We wanted to better understand how long patients experienced symptoms before they sought medical attention (this is of course with the benefit of 20/20 hindsight). Some 37.6% of respondents sought treatment early, waiting six months or less. However, nearly half — approximately 46% — experienced symptoms anywhere from six months to three years before their first doctors visit.

 

We asked respondents the types of treatments they had undergone since diagnosis. A significant 77.8% had various types of drug therapy and 37% received a stem cell transplant. A number of the patients having a stem cell transplant also had drug therapies, so these responses are not exclusive of one another.

 

For those who underwent a stem cell transplant, we wanted to understand whether the procedure was done as an inpatient, an outpatient, or as a combination. The majority at 68.5%, for a variety of reasons, were inpatient.

 

Our next category of questions focused on clinical trials.  Of our 575 respondents, roughly one-quarter have participated in a clinical trial.

 

We asked those who participated in a clinical trial which one they were in. You can see below the distribution for the ATTR trials. We did ask a separate question regarding the AL-focused trials, however the data proved to be questionable and thus it was excluded from this recap.

 

The next question was aimed at the 77% who indicated they did not participate in a clinical trial, seeking to understand why not.  Striking was the number of respondents who declined, for whatever reason, to answer.

 

In the next question we asked respondents to provide some insight into how they rated their ability to tolerate treatment, whatever that may be. It was spread out, perhaps due to a wide range of treatments.

 

We then asked patients to assess their quality of life before and after treatment. For those that responded, the majority indicated at least a moderate improvement.

 

 

In our next-to-last question we asked the current state of their disease.

 

The final question was open-ended, where we asked respondents to complete the following sentence: “With hindsight, I would have appreciated knowing about …”  We received a massive number of responses, and in our desire to give everyone their full and unedited voice, we invite you to read through the many heartfelt and authentic voices (listed in the order received).   “With hindsight, I would have appreciated knowing about …”

 

 

CLOSING THOUGHTS

 

The responses we got from this study reinforce the complexity and diversity of amyloidosis. To each member of this community who stepped forward to answer the questions, we thank you. Gathering information, spreading awareness, and pushing for change leads us on the path to earlier diagnosis and an increase in life-saving research.

 

One repeating point people mentioned in the last question was a need for more information for doctors and members of the medical community, and for patients and caregivers who are dealing with this disease. If we continue to reach out to doctors, they will recognize the symptoms of amyloidosis and will think to test for it, leading to earlier diagnosis. If we continue to provide patients and caregivers with the most up to date information on treatments, resources, and where they can go for support, we can help arm those who are newly diagnosed. In this way, the sharing of information can be one of our most valuable tools.

 

Fight on, amyloidosis warriors. Fight on.

 

Clinical Trials 101

Clinical research is simply medical research involving people. There are two types, clinical studies (aka observational studies) and clinical trials. In this blog, we explore clinical trials and the basics of what you need to know.

 

WHAT ARE CLINICAL TRIALS?

According to the National Institutes of Health (NIH), clinical trials are research studies performed on people that are aimed at evaluating a medical, surgical, or behavioral intervention. Clinical trials are the primary way that researchers find out if a new treatment, like a new drug or medical device (e.g., a pacemaker) is safe and effective in people. Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment. Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still, others test ways to prevent a health problem before it begins. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem.

 

WHY CLINICAL TRIALS ARE IMPORTANT

Clinical trials permit researchers to test the safety and effectiveness of new therapies. They also allow for a rigorous evaluation through patient participation. Bottom line: it is only after the extensive evaluation and testing from a clinical trial that the FDA will approve the widespread use of any new therapy.

According to Dr. Morie A. Gertz at the Mayo Clinic:

Advancing the medical care for all patients requires participation in clinical trials. Only through clinical trials can we further improve the available therapy options for current and all future patients. Clinical trials seek to answer questions about the natural history and biology of the disease as well as important questions regarding outcomes was all available new therapies. All current treatments received by our amyloid community were derived through others participation in clinical trials. Clinical trials are not only an opportunity to get the cutting edge therapy but is a way to “pay it forward“ for future generations of Patients.

 

WHAT ARE THE PHASES OF CLINICAL TRIALS?

All clinical trials must be approved by the U.S. Food and Drug Administration (FDA) before they can begin. Prior to that decision, scientists perform laboratory tests and studies in animals to test a potential therapy’s safety and efficacy. Assuming favorable outcomes, the FDA then gives approval for a clinical trial involving humans.

Clinical trials are comprised of four phases to test a treatment, find appropriate dosages, and detect side effects. If following the completion of the first three phases, researchers find the drug or intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its effects. Overall, the duration of a clinical trial spans years.

  • A Phase I trial tests an experimental treatment on a small group of often healthy people (20 to 80) to judge its safety and side effects and to find the correct drug dosage.
  • A Phase II trial uses more people (100 to 300). While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. These trials also continue to study safety, including short-term side effects. This phase can last several years.
  • A Phase III trial gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people. If the FDA agrees that the trial results are positive, it will approve the experimental drug or device.
  • A Phase IV trial for drugs or devices takes place after the FDA approves their use. A device or drug’s effectiveness and safety are monitored in large, diverse populations. Sometimes, the side effects of a drug may not become clear until more people have taken it over a longer period of time.

 

WHY PEOPLE CHOOSE TO JOIN A CLINICAL TRIAL

There are many reasons why people choose to join a clinical trial. Some join a trial because the treatments they have tried for their health problem did not work. Others participate because there is no treatment for their health problem. Some studies are designed for, or include, people who are healthy but want to help find ways to prevent a disease that may be common in their family. By being part of a clinical trial, participants may access new treatments before they are widely available. Especially with a rare disease such as amyloidosis, clinical trials may offer a meaningful impact to a patient’s quality of life.

In addition, people may feel that participating in a clinical trial allows them to play a more active role in their own health care. Participants may receive more frequent health check-ups and closer monitoring through the clinical trial. Other people say they want to help researchers learn more about certain health problems. Whatever the motivation, when choosing to participate in a clinical trial, one becomes a partner in scientific discovery. This can also help future generations lead healthier lives. Major medical breakthroughs could not happen without the generosity of clinical trial participants—young and old.

In the words of Dr. Vaishali Sanchorawala at The Amyloidosis Center at Boston University School of Medicine and Boston Medical Center:

Clinical trials allow researchers and physicians to test the safety and effectiveness of new, promising drugs. Before any drug can be approved, it must be rigorously tested in clinical trials. Without the participation of patients, new treatments and cures will never happen. In addition, participating in a clinical trial may be a great way for patients to access new treatments before they become available. Especially in a rare disease such as amyloidosis, clinical trials can be a vital resource for the care of patients.

 

POTENTIAL RISKS OF A CLINICAL TRIAL

There are no guarantees of success from a clinical trial, and there are risks. For starters, there may be serious side effects. Also, the therapy may not improve upon current treatment, or may not even work at all. Finally, as a clinical trial participant, you may be part of the control group, which means either standard treatment or no-treatment placebo. In other words, there are no assurances you would receive the new therapy.

 

FINDING A CLINICAL TRIAL

Thanks to the internet, folks can find lots of information regarding the wide array of open clinical trials. So much so that it may be overwhelming. Particularly with regards to amyloidosis, casting such a wide net may not be the most productive approach. Since finding an appropriate clinical trial is not as easy for rare diseases such as amyloidosis, here are a few excellent places to start.

  • My Amyloidosis Pathfinder (MAP). Developed by the Amyloidosis Research Consortium (ARC), MAP helps patients discover and learn about amyloidosis-related clinical trials. After answering a short questionnaire, MAP matches patients to trials specific to their condition and ones for which they may be eligible.
  • Boston University / Boston Medical Center. A recognized Center of Excellence for amyloidosis, BU has an ongoing robust array of clinical trials for different types of amyloidosis.
  • Mayo Clinic. A recognized Center of Excellence for amyloidosis, Mayo Clinic has an extensive clinical trial program in the area of amyloidosis.
  • ClinicalTrials.gov. This resource, provided by the U.S. National Library of Medicine, is a database of over 250,000 privately and publicly funded clinical studies conducted around the world (in all 50 states in the U.S. and 204 countries).

 

INFORMED CONSENT PROCESS

The informed consent process is a key part of the safeguard of a clinical trial. Before joining a clinical trial, each participant will be told what to expect (e.g., treatments, tests) and what might happen (e.g., benefits and risks, including possible side effects). It is also the point where participants should ask ample questions about the trial, which the clinical trial coordinator should be more than willing to answer.

Below is a list of questions compiled from sources, including the NIH and The Clinical Study Center, recommending what patients should consider asking before consenting to participation in a clinical trial.

  • What is the purpose of the study?
  • Who is sponsoring the study, and who has reviewed and approved it?
  • Who will be in charge of my care?
  • What treatment or tests will I have? Will they hurt?
  • What are the chances I will get the experimental treatment?
  • What are the possible risks, side effects, and benefits of the study treatment compared to my current treatment?
  • How will I know if the treatment is working?
  • How will you protect my health while I am in the study?
  • What happens if my health problem gets worse during the study?
  • How will the study affect my everyday life?
  • How long will the clinical trial last?
  • What will happen after the conclusion of the study?
  • Where will the study take place? Will I have to stay in the hospital?
  • Will you provide a way for me to get to the study site if I need it?
  • Will being in the study cost me anything (e.g., treatment, tests, travel)? If so, will I be reimbursed for all expenses (including other charges such as child care)? Will my insurance cover my costs?
  • Can I take my regular medicines while in the trial?
  • Who will be in charge of my care while I am in the study? Will I be able to see my own doctor?
  • Will you follow up on my health after the end of the study?
  • Will you tell me the results of the study?
  • Whom do I call if I have more questions?
  • How will you keep my doctor informed about my participation in the trial?
  • Does the study compare standard and experimental treatments?
  • If I withdraw, will this affect my normal care?
  • What are the chances that I will receive a placebo?
  • What steps ensure my privacy?

 

Taking part in a clinical trial is solely the decision of the participant, although they may want to discuss it with their medical team prior to finalizing a decision. If one decides to join the trial, they will be required to sign an informed consent form that presents the key facts of the study and indicates they have been told all of the details and want to be part of the study. Importantly, the informed consent form is NOT a contract. Participants can leave the trial at any time and for any reason without being judged or put in a difficult position regarding medical care. Researchers much keep health and personal information private. Also, during the trial, participants have the right to learn about new risks or findings that emerge.If researchers learn that a treatment harms any of the participants, they’ll be removed from the study.

 

PARTICIPANT PROTECTION & SAFETY

Before committing to participate in a clinical trial, it is important to understand participant safety. Congress has put laws in place to protect against abuses, and today every clinical investigator is required to monitor and make sure that every participant is safe. These safeguards are enforced by the Federal Government. Every clinical trial follows a protocol that describes what the researchers will do. The principal investigator, or head researcher, is responsible for making sure that the protocol is followed.

In addition, there are multiple scientific oversight groups to aid in the control of clinical trials.

  • Institutional Review Board (IRB): Comprised of doctors, scientists, statisticians, and lay people, IRBs provide scientific oversight for all clinical trials in the United States. IRB members regularly review studies and their results, making sure risks (or potential harm) are minimized.
  • Office for Human Research Protections (OHRP): The U.S. Department of Health and Human Services’ (HHS) Office for Human Research Protections (OHRP) oversees all research done or supported by HHS. The OHRP helps protect the rights, welfare, and well-being of research participants. They provide guidance and oversight to the IRBs, develop educational programs and materials, and offer advice on research-related issues.
  • Data Safety Monitoring Board (DSMB): Comprised of research and study topic experts, this board is required for every NIH phase III clinical trial. Their role is to review data from a clinical trial for safety problems or differences in results among different groups of relevant studies. If they find that the experimental therapy is not working or is harming participants, they will halt the trial right away.
  • Food and Drug Administration (FDA): In the United States, the FDA provides oversight for clinical trials that are testing new medicines or medical devices. They review applications before any testing on humans is done, checking to ensure a proposed clinical trial has proper informed consent (see earlier) and protection for human subjects. In addition, the FDA provides oversight and guidance at various stages throughout the trial.

 

Scientific oversight informs decisions about a trial while it’s underway. For example, some trials are stopped early if benefits from a strategy or treatment are obvious. That way, wider access to the new strategy can occur sooner. Sponsors also may stop a trial, or part of a trial, early if the strategy or treatment is having harmful effects. Protecting the safety of people who take part in clinical trials is a high priority for all involved. Each trial has scientific oversight, and patients also have rights that help protect them.

 

DECIDING WHO PARTICIPATES IN CLINICAL TRIALS

After signing the informed consent form, the clinical staff will screen the candidate against the clinical trial criteria. The screening may involve cognitive and physical tests. Inclusion criteria for a trial might include age, stage of disease, gender, genetic profile, family history, and whether or not the candidate has a study partner who can accompany them to future visits. Exclusion criteria might include factors such as specific health conditions or medications that could interfere with the treatment being tested. Generally, individuals can participate in only one trial or study at a time. Different trials have different criteria, so being excluded from one trial does not necessarily mean exclusion from another.

Clinical trials need numbers … many volunteers must be screened to find enough people for a study, and with rare diseases such as amyloidosis, important trials are often significantly delayed due to a lack of participants. This can seriously slow down the rate at which new drugs are discovered, tested, and made available to patients.

 

CONCLUSION

Not all clinical trials have successful outcomes. However, every disease-related drug and therapy treatment prescribed today is the result of clinical research. Clinical trials are absolutely necessary to determine that a treatment is safe and that it has a real positive effect on a particular disease, better than that observed by a placebo or the current standard of care.

Final thoughts from Isabelle Lousada, founder and CEO of Amyloidosis Research Consortium:

Clinical trials play a critical role in evaluating novel therapies, establishing the best treatment pathways, and increasing our knowledge about amyloidosis.

 

SOURCES

Amyloidosis Research Consortium

Boston University / Boston Medical Center, Amyloidosis Center

The Clinical Study Center

Mayo Clinic

National Institute on Aging

National Institutes of Health

U.S. National Library of Medicine

 

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