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General background and terminology
Clinical studies
The aim of all clinical studies is to increase medical knowledge by performing research in human volunteer participants. There are two types of clinical studies:
- Observational studies
- Clinical trials
Observational studies
Observational studies involve structured assessment and follow up evaluation of health outcomes in a group of patients over time. The investigators performing an observational study do not assign the patients to a particular treatment or intervention, as occurs in a clinical trial. Observational studies add to our understanding of the natural history of a disease and give us information about how patients are treated and how they respond to treatments. For example, the AL Chemotherapy (ALchemy) study at the NAC has gathered 'real world' data on all UK patients diagnosed with AL amyloidosis at the NAC, including the treatment regimes they have received, the side effects experienced and the patient outcomes.
Clinical trials
Clinical trials involve evaluation of the effects of specific interventions on human participants. Often new drugs or interventions are compared to dummy drugs known as placebos. Sometimes a new drug is compared to an existing drug. Researchers follow all participants carefully to assess the effects of the trial drug. Drug development is a highly regulated and ordered process, consisting of a series of clinical trial steps called phases. Each phase is designed to address a different research question, and all new drugs are required to proceed through all the phases in an orderly fashion.
Phase 1 trials:
Initial safety trials on a new drug in humans. The aim of phase 1 trials is to evaluate common side effects, to look at how the human body metabolises the drug and to establish a tolerated dosage range. Participants are often healthy volunteers.
Phase 2 trials:
Phase 2 trials usually involve a small number of patients with the condition being studied. These trials evaluate drug safety in these patients and gather preliminary data on effectiveness.
Phase 3 trials:
Phase 3 trials are conducted after the drug has been demonstrated as effective in small numbers of patients with the condition studied. These trials usually involve a large number of patients with the condition. These trials provide more data on the effectiveness and safety of the drug in patients with the condition being studied. If the data from phase 3 trials are sufficient, then researchers may use it to apply to the licensing authorities for marketing approval.
Phase 4 trials:
Phase 4 trials are post-marketing trials carried out after a drug has received regulatory approval. These trials gather additional information about the safety and effectiveness of the drug.
Some other terms used in clinical studies
Randomised controlled trial
This means that a number of similar people are randomly assigned to two or more groups. One group (the experimental group) receives the drug being tested. The other (the control group) receives either a dummy treatment (placebo), an alternative treatment or no treatment. Researchers follow both groups to compare the outcomes in the experimental group and the control group.
Placebo
A dummy or sham treatment, received by the patients in the control group of a controlled clinical trial.
Double blind
This means that neither the patients nor the researchers know who is receiving the study drug and who is receiving placebo. Drug and placebo materials are coded by an independent third party who holds the code secretly until the study is completed or a significant adverse effect requires 'unblinding.'
Open label
This means that both the patients and the researchers know what drug and what dose is being administered.
Multicentre
This means that the trial includes patients and researchers in a number of different sites, often from all around the world.
Informed consent
This is the procedure whereby the researchers explain all the important information about the study to the patient. They ensure that the patient understands the risks and benefits and that enrolment is voluntary. The patient then signs an informed consent form.
Prospective studies
In prospective studies, a group of people is recruited and then followed over a period of time, in order to gather data regarding a specific study question. For example the ALchemy study, discussed in more detail below, is a prospective observational study. Patients with a diagnosis of systemic AL amyloidosis requiring chemotherapy treatment are recruited at the NAC at the time of diagnosis. Routine clinical data are then collected over time to give information on treatment, treatment toxicity and outcomes in these patients.
In prospective drug trials, patients are recruited and then followed over a period of time while they receive a study drug. Sometimes patients receiving the study drug are compared to similar patients receiving an older, established drug, or to patients receiving a placebo. Patient data collected over time provides information that can be analysed to assess the effect of the study drug.
Retrospective studies
In retrospective studies, data that have already been collected through medical records or in a clinical study are analysed in order to address a new question that the original study was not designed to address. For example, in a recent publication co-authored by the NAC consultants and by European colleagues, treatment outcomes in patients with advanced cardiac AL amyloidosis were evaluated retrospectively. Data on these patients were extracted from patient records and analysed. The results provided new information on outcomes in this particular patient group, which had not previously been assessed as distinct from the overall outcomes in all AL amyloidosis patients.
Terms used in AL amyloidosis trials
Response to chemotherapy treatment for AL amyloidosis may be assessed by the following criteria:
Haematological response - the response of the abnormal plasma cells producing amyloidogenic free light chains in the bone marrow. This assessment includes:
- Measurement of concentrations of free light chains in blood tests (serum) and in urine.
- Bone marrow biopsy.
Organ response - assessment of the body organs that contain amyloid deposits.
The different categories of haematological response are defined as follows:
Complete response (CR)
- No monoclonal protein in blood tests (serum) and urine tests.
- Normal free light chain ratio (ratio of amyloidogenic free light chains to non-amyloidogenic light chains).
- Absence of identifiable clonal plasma cells in bone marrow biopsy.
Partial response
- 50% reduction in serum M component (monoclonal protein) if concentration is over 0.5 g/dL.
- 50% reduction in urine light chain concentration if there is a visible light chain peak in the urine and over 100 mg/day.
- 50% reduction in serum free light chain (FLC) concentration if FLC concentration is over 10 mg/dL.
Trials taking place at the NAC
Trials for AL amyloidosis
ALchemy
The ALchemy (AL amyloidosis chemotherapy) study is a large, on-going, 'real world' study of chemotherapy in systemic AL amyloidosis, funded by a grant from the charity Myeloma UK. The NAC started this study in 2009 in order to address several unanswered questions relating to patients with AL amyloidosis.
An unmet need
Prior to ALchemy, there had been no large systematic studies following and monitoring patients with systemic AL amyloidosis from the time of diagnosis (prospective studies). Studies that had been carried out were small and usually did not include patients with severe disease. Many patients were lost to follow up after their initial visits to the NAC. It was therefore hard to assess accurately exactly which chemotherapy treatments patients around the country were receiving, what side effects they experienced and how the disease and treatment impacted on their quality of life. ALchemy aimed to fill these gaps in our knowledge and to help us to improve our clinical practice accordingly. Our goal was to gain a 'real world' picture of the disease by close monitoring of all patients with systemic AL amyloidosis regardless of age or disease severity.
Who is eligible for ALchemy?
All patients diagnosed with systemic AL amyloidosis in need of treatment are eligible for enrolment in ALchemy if they are able and willing to give informed consent and have had no (or minimal) prior therapy.
ALchemy monitoring
Patients enrolled in the study are monitored closely by NAC clinical research nurses. Before ALchemy started, our standard follow up protocol involved an NAC assessment at diagnosis then every 6 months.
The ALchemy protocol involves:
- Evaluation of patients' response to treatment after 3 months, after just 3 cycles of treatment.
- Requesting that the patients' local treating physicians and nurses supply us with data regarding chemotherapy and other treatments and side effects after every cycle (every month). We provide a form for the data.
- Requesting that patients send us blood samples after every cycle (every month) so we can check free light chain (FLC) concentrations and serum protein electrophoresis (SPE). We provide the blood sample tubes and pre-addressed padded envelopes and patients can go to their GP or local hospital clinic to have the blood drawn.
We wanted to assess the feasibility of this intensive, early monitoring approach. We also wanted to evaluate whether such early assessments could lead to better treatment outcomes.
ALchemy has already led to improved patient care
Soon after the ALchemy study began, it became clear that patients were benefiting from the more intensive monitoring with the extra appointment after the first 3 cycles of chemotherapy, monthly blood samples and treatment forms from the local doctors. As a result, we have incorporated all of these into our standard clinical practice for all patients.
Tourmaline AL 1
The trial
This is an international randomised phase 3 trial of a new drug - MLN9708, in patients with AL amyloidosis with relapsed or refractory disease. MLN9708 belongs to the drug class called proteasome inhibitors. This drug class also includes bortezomib, a drug which is often effective treatment for AL amyloidosis. Patients with relapsed disease have responded to a chemotherapy treatment regime in the past, but after a while the AL amyloidosis has worsened again despite continued treatment. Refractory disease means that patients have not responded to the treatment regime they received. This trial aims to find out if patients with relapsed and refractory AL amyloidosis respond better to treatment with MLN9708 plus dexamethasone than to other chemotherapy regimes.
What the trial involves for patients
In order to compare the effects of MLN9708 plus dexamethasone to the effects of other chemotherapy regimes that doctors usually select for patients with relapsed or refractory AL amyloidosis, each patient taking part in the trial is randomly assigned to one of the following two groups:
Experimental (MLN9708 plus dexamethasone). Patients will receive MLN9708 (4.0 mg) orally (PO) on days 1, 8, and 15 plus dexamethasone 20 mg/day PO weekly on days 1, 8, 15, and 22 of each 28-day cycle; dexamethasone may be increased up to 40 mg/day after 4 weeks, if tolerated.
Active comparator (doctor's choice). Patients will receive one of the following regimes as selected by their doctor:
- Dexamethasone: 20 mg/day orally (PO) on days 1-4, 9-12 & 17-20 of each 28-day cycle.
- Dexamethasone + melphalan: dexamethasone 20 mg/day PO on days 1-4 of each 28-day; plus melphalan 0.22 mg/kg PO on days 1-4 every 28 days.
- Dexamethasone + cyclophosphamide: dexamethasone 20 mg/day PO weekly on days 1, 8, 15 & 22 of each 28-day cycle; plus cyclophosphamide 500 mg PO on days 1, 8 & 15 every 28 days.
- Dexamethasone + thalidomide: dexamethasone 20 mg/day PO weekly on days 1, 8, 15 & 22 of each 28-day cycle; plus thalidomide total dose up to 200 mg/day PO.
- Dexamethasone + lenalidomide: dexamethasone 20 mg/day PO weekly on days 1, 8, 15 & 22 of each 28-day cycle; plus lenalidomide 15 mg/day for 21 days every 28 days.
Who can take part in the trial
Patients with systemic AL amyloidosis affecting the heart and/or kidneys who have received one or two previous lines of treatment, and who have not received bortezomib first line, are eligible for participation in this trial.
Outcomes
The following outcomes will be assessed in this trial:
- Overall response rate (ORR) - this will include estimation of what proportion of patients have complete response (CR), a very good partial response (VGPR) or a partial response (PR) to treatment. Response is assessed with the blood test which measures the free light chain (FLC) concentration. The better the response to treatment, the greater the drop in FLC concentration.
- Hospitalisation rates for heart failure or progression to end state kidney disease or death after 2 years.
In addition, the overall survival (OS), progression free survival (PFS), the safety and the number of patients with heart and/or kidney response will be assessed.
Timing
This study is ongoing at the NAC, Oxford, Birmingham and Manchester.
A study of genotype and phenotype in plasma cells in patients with AL amyloidosis
The study
This study will assess the characteristics of abnormal bone marrow plasma cells in patients with AL amyloidosis.
Background
Treatment of AL amyloidosis is chemotherapy targeting abnormal bone marrow plasma cells. The characteristics of these cells determines the treatment outcomes. This study seeks to characterise in detail the abnormal plasma cells by flow cytometry, DNA analysis and exome sequencing.
What the trial involves for patients
All patients with AL amyloidosis need a bone marrow test as a part of the diagnostic work up for amyloidosis and for response assessment at the end of treatment. This study seeks an additional bone marrow sample as well as the usual diagnostic sample.
Who can take part in the trial
Patients with systemic AL amyloidosis may participate in this trial, starting either at the time of diagnosis or after completion of treatment.
Outcomes
It is hoped that the detailed analysis of genetic and other characteristics of abnormal plasma cells in patients with AL amyloidosis will improve understanding of development of disease and response to treatment.
Timing
This study is ongoing at the NAC.
Targeted radiotherapy for AL amyloidosis (TRALA)
Background
The most effective treatment available for AL amyloidosis is high dose chemotherapy which kills the abnormal cells in the bone marrow. This treatment is also toxic to the normal bone marrow cells, so patients who receive high dose chemotherapy need to undergo autologous stem cell transplantation, where normal bone marrow cells are collected from the patient before chemotherapy then reinfused after chemotherapy.
This treatment can be very effective, but the high dose chemotherapy may be associated with serious adverse effects. The TRALA study will investigate the use of targeted radiotherapy to destroy the bone marrow cells instead of high dose chemotherapy. Patients will undergo stem cell transplantation, as with high dose chemotherapy. It is hoped that the targeted radiotherapy will be as effective as high dose chemotherapy in destroying the abnormal bone marrow cells that cause AL amyloidosis, with less severe side effects. Targeted radiotherapy means that the radiation is given directly to the bone marrow using a radiolabelled antibody. This avoids exposure of healthy organs to radiation.
The trial
This is a phase 1/2a study to assess the use of targeted radiotherapy with [90Y]-labelled anti-CD 66 (anti CD66 antibody radiolabelled with Yttrium 90) as the sole conditioning prior to autologous stem cell transplant in patients with AL amyloidosis.
What the trial involves for patients
In order to assess the safety and toxicity associated with use of [90Y] –labelled anti-CD 66 to treat AL amyloidosis and to determine the optimal radiation dose that can be delivered safely to patients with AL amyloidosis, patients will undergo:
- An initial dosimetry and imaging hospital visit to determine the radiation dose that will be given. This visit will involve administration of a different radiolabelled drug (CD66 radiolabelled with Indium-111), followed by scans 1, 3 and 4 days later.
- About 1 week later, harvesting of the patient’s stem cells followed by administration of the study treatment with [90Y]-labelled anti-CD 66, then subsequent re-infusion of the patient’s stem cells (autologous stem cell transplantation).
- Examination and testing by the study doctors 30 days and 100 days after stem cell transplantation.
There will be three treatment levels with step-wise increase of the infused [90Y]-labelled anti-CD66 radiation activity which will be given prior to autologous stem cell transplantation. The total number of participants planned is between 12-18.
Who can take part in the trial
Patients with systemic AL amyloidosis with an indication for treatment who satisfy all standard autologous stem cell transplantation inclusion criteria (good organ function, no significant heart involvement, good performance status).
Outcomes
The primary outcomes assessed in this trial will be the safety and toxicity associated with the use of [90Y]-labelled anti-CD66 and establishment of the maximum tolerated radiation dose (MTD) over three infused radiation activity levels. Other outcomes assessed (secondary outcomes) will include assessment of clonal response, disease response, cardiac recovery, time to progression and overall survival.
Timing
This study is open for recruitment at the NAC.
Dose escalation study of carfilzomib taken with thalidomide and dexamethasone in relapsed AL amyloidosis (CATALYST)
Background
The most effective treatment available for AL amyloidosis is high dose chemotherapy followed by autologous stem cell transplantation (ASCT). However this treatment is only appropriate for patients with limited organ involvement, younger age and good functional status. The majority of patients with AL amyloidosis are not candidates for ASCT and are treated with combination chemotherapy, often including bortezomib, a proteasome inhibitor. Bortezomib is particularly effective in AL amyloidosis but may have severe side effects. Carfilzomib, a different drug from the proteasome inhibitor class, appears to be better tolerated than bortezomib, with fewer side effects. However information on carfilzomib in AL amyloidosis treatment is limited. The CATALYST study will investigate safety, efficacy and dosing of carfilzomib in patients with AL amyloidosis.
The trial
This is a phase 1/1a dose escalation study to investigate safety and efficacy of carfilzomib in combination with thalidomide and dexamethasone, in patients with relapsed or refractory AL amyloidosis. The trial starts with a dose escalation phase to determine maximum tolerated and recommended dose. There will then be an expansion phase to assess efficacy.
What the trial involves for patients
Participants in the escalation phase will receive up to six cycles of treatment with carfilzomib thalidomide and dexamethasone in combination. Carfilzomib will be administered on day 1, 8, and 15, with four groups of patients each receiving different doses of carfilzomib. Following determination of the maximum tolerated dose and recommended dose, the trial will be opened to an expansion phase where participants will receive the recommended dose of carfilzomib, along with thalidomide and dexamethasone. Patients will initially undergo screening assessments at the National Amyloidosis Centre, including a physical examination, laboratory tests, a pregnancy test, an echocardiogram, a 24 hour Holter monitor test, a bone marrow examination (if the doctors think this is necessary), and an assessment of medical history. They will then be referred to their local participating hospital, where some of these assessments will be repeated. If the patient can go on to the trial, they will need to visit their local participating hospital on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles of treatment. At every treatment visit, patients will have blood tests, and at the end of cycle 2, another echocardiogram. In the course of the study, patients will also undergo further assessment sessions at the National Amyloidosis Centre.
Who can take part in the trial
Patients with systemic AL amyloidosis with relapsed or refractory disease after chemotherapy or ASCT.
Outcomes
The primary outcome measures are:
- Assessment of dose-limiting toxicities to establish the maximum tolerated dose of carfilzomib.
- Determination of proportion of patients receiving carfilzomib who experience severe (Grade 3/4) toxicity.
Secondary outcome measures include clonal response rates after 3 and 6 months and organ response rate.
Timing
The study is ongoing at the NAC.
A study to evaluate the efficacy and safety of daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared to CyBorD alone in newly diagnosed systemic amyloid light-chain (AL) amyloidosis
Background
Cyclophosphamide, bortezomib and dexamethasone (CyBorD) is standard therapy received by many patients with newly diagnosed systemic AL amyloidosis. Daratumumab is an approved agent for treating multiple myeloma via intravenous infusion. It is not a chemotherapy drug; it belongs to the relatively new class of drugs called targeted therapy. It is an antibody targeting a cell surface protein called CD38, which is found on the abnormal plasma cells that cause myeloma and AL amyloidosis. Daratumumab treatment, in combination with standard chemotherapy, has shown good efficacy in treating myeloma, and preliminary trials in AL amyloidosis have also been encouraging.
Daratumumab is usually given intravenously, which may be challenging for patients with AL amyloidosis whose hearts may be adversely affected by receiving fluids intravenously. In this trial, daratumumab is administered in a novel way by subcutaneous injection, which is hoped to be safer and more effective for patients with AL amyloidosis.
The trial aims to compare outcomes in newly diagnosed patients with AL amyloidosis treated with CyBorD alone to those treated with CyBorD and daratumumab. The study is designed to allow stem cell collection after the first 6 months of therapy so that stem cell transplantation may be considered in the future.
The trial
This is a phase 3 trial, to test the primary hypothesis that daratumumab in combination with CyBorD will improve the overall haematological response rate compared to CyBorD alone in patients with AL amyloidosis. Participants are expected to be involved in the trial for around 8 years, which will include a screening phase, treatment phase, post-treatment observation phase and long-term follow up phase.
What the trial involves for patients
The screening phase will involve complete clinical evaluation. In the treatment phase, participants in the experimental group will receive dexamethasone followed by subcutaneous daratumumab, followed by cyclophosphamide and bortezomib on weekly treatment days in every 28 day cycle for a maximum of 6 cycles. Daratumumab will be administered weekly for the first 8 weeks, then every two weeks for 4 cycles, then every 4 weeks until disease progression or subsequent therapy for a maximum of 2 years. Participants in the active comparator arm will receive the same treatment with CyBorD but without daratumumab. During the treatment phase, adverse events and clinical response will be monitored, during the post treatment observation phase disease evaluations will be performed, and during the long term follow up phase subsequent treatment, treatment response, and clinical status will be followed.
Who can take part in the trial
Patients with newly diagnosed systemic AL amyloidosis. For a full list of exclusion criteria, see the www.clinicaltrials.gov website.
Outcomes
The primary outcome measure is percentage of participants with overall complete haematological response. Secondary outcome measures include progression-free survival, organ response rate, overall survival, change in cancer quality of life questionnaire scores.
Timing
The study is ongoing at UCL.
Trials for ATTR amyloidosis
Brief background on ATTR amyloidosis
Amyloidosis is a disorder of protein folding, where normally soluble proteins misfold and form abnormal, insoluble amyloid fibrils, which deposit in the tissues and accumulate to damage the structure and function of tissues and organs.
Transthyretin (TTR) is a normal blood protein which transports thyroid hormones and retinol (vitamin A), hence its name ‘trans-thy-retin’. All TTR in the blood is produced in the liver; TTR is also produced in the brain and eye but does not reach the blood from there. In ATTR amyloidosis, the amyloid deposits in the organs contain amyloid fibrils formed from misfolded TTR protein.
Hereditary ATTR amyloidosis is caused by a mutation in the gene for TTR, inherited from one parent. The disease therefore runs in families, though the timing, development and severity of the disease can vary greatly.
In acquired (non-hereditary) ATTR amyloidosis, the amyloid is formed by the normal, so‑called ‘wild-type’ protein. This disease is not hereditary. It is known as wild-type ATTR (ATTRwt) amyloidosis (formerly called senile systemic amyloidosis (SSA)).
The clinical presentation and effects of ATTR amyloidosis vary widely depending on which organs are mostly affected.
Hereditary ATTR amyloidosis - 'variant' ATTR amyloid deposits
People with mutations in the TTR gene produce abnormal, amyloidogenic, ‘variant’ TTR throughout their lives. The genetic mutations in ‘variant’ TTR destabilise the TTR protein and greatly promote its inherent amyloid forming potential. Amyloid deposits start to form and then build up until they cause clinical disease, mainly affecting the nerves and/or heart, and sometimes the kidneys, eyes and synovial tissues (tendons and ligaments). Symptoms may appear at any time from early adult life onwards. This condition runs in families.
Hereditary ATTR amyloidosis was traditionally referred to as familial amyloid polyneuropathy (FAP) when disease mainly affected the nerves or familial amyloid cardiomyopathy (FAC) when disease mainly affected the heart. However it is now understood that in clinical practice there is significant overlap in disease manifestations not only between patients with different mutations but also among those with the same mutation. Most TTR mutations can cause amyloid deposits in both the nerves and the heart. The International Society of Amyloidosis has therefore recommended the use of the term hereditary ATTR amyloidosis to describe disease caused by ATTR amyloid deposits in all patients with TTR gene mutations.
Hereditary ATTR amyloidosis is the most commonly recognised form of hereditary systemic amyloidosis but it is nevertheless a very rare disease. More than 150 amyloidogenic variants (mutations) of TTR have been observed and different mutations may cause different disease manifestations.
Despite being extremely rare in most parts of the world, hereditary ATTR amyloidosis is common in some very localised parts of Portugal, Sweden and Japan. It may also be common, but under-diagnosed in several other regions including Spain, France, Brazil, Argentina, Cyprus, Bulgaria and Ireland.
Hereditary ATTR amyloidosis is sometimes seen in people living in the UK, with ancestors from these regions.
'Wild-type' ATTR amyloidosis - non-hereditary
Normal, 'wild-type' TTR may also be amyloidogenic. Microscopic deposits of ‘wild-type’ ATTR amyloid are very common in the elderly, and have been found in one in four autopsies of people aged over 80. Until recently it was thought that these ‘wild-type’ ATTR amyloid deposits hardly ever caused disease. However, new imaging techniques have shown that in fact, disease caused by ‘wild-type’ ATTR deposits may be far commoner than anyone thought. This disease was formerly known as senile systemic amyloidosis, or senile cardiac amyloidosis. Amyloid deposits consisting of ‘wild-type’ TTR mainly affect the heart but may also cause carpal tunnel syndrome, backpain from lumbar canal stenosis, and bleeding from the bladder in some people. ‘Wild-type’ ATTR amyloidosis is not hereditary (it does not run in families). Most patients with this condition are men aged over 70 but it can also present as young as 50 years.
Drugs for ATTR amyloidosis
Two new drugs (patisiran and inotersen) have recently been granted a license for treatment of hereditary ATTR amyloidosis with neuropathy (i.e., with nerve involvement). They are both undergoing evaluation by NICE/NHS England with respect to funding in the UK. Other disease-modifying drugs are in varying stages of development and licensing.
The TRANSCEND study
The full name of this study is: TRansthyretin Amyloidosis: Neuropathy, Senility, Cardiomyopathy, Evaluation, Natural history and Diagnosis.
The goal of TRANSCEND is to achieve a 'real world' picture of ATTR amyloidosis in the UK by close monitoring of all patients with ATTR amyloidosis, regardless of age or disease severity.
The TRANSCEND study will include patients seen at the NAC with all types of ATTR amyloidosis.
ATTR amyloidosis: filling in the gaps in our knowledge
Hereditary ATTR amyloidosis
The FAP World Transplant Registry (FAP WTR) was established in 1995, in order to compile data on survival of patients who undergo liver transplantation for hereditary ATTR amyloidosis (previously known as FAP) and to determine the optimal time for liver transplantation. Most patients worldwide who have undergone liver transplantation for hereditary ATTR amyloidosis carry a single TTR mutation, Val30Met, which is rare in the UK. There is a relative lack of data on the natural history of hereditary ATTR amyloidosis in association with the other disease-causing TTR gene mutations.
We now know that liver transplantation does not prevent continued build-up of ATTR amyloid in the heart. There is a need for careful cardiac follow-up of patients who have undergone liver transplantation for hereditary ATTR amyloidosis, to enhance our understanding of this process.
'Wild-type' ATTR amyloidosis and amyloid cardiomyopathy
Newly available cardiac imaging techniques (cardiac magnetic resonance imaging and DPD scintigraphy) have resulted in greatly increased diagnoses of cardiac ATTR amyloidosis. There has been a 40-fold increase in the number of referrals of patients to the NAC with ‘wild-type’ ATTR amyloidosis over the past decade.
ATTR amyloidosis may be a relatively common cause of heart failure in the elderly. There is a need to follow these patients systematically in order to learn about the natural history of this emerging condition, and to increase awareness of the condition throughout the UK.
Quality of life (QOL)
At present there are no standard, accepted measures of QOL for ATTR amyloidosis. TRANSCEND aims to establish and validate such measures, by following QOL throughout the disease course. QOL measures will also be important when assessing the effects of new drugs for ATTR amyloidosis.
New treatments
There are a number of drugs for ATTR amyloidosis currently in various stages of development. In order to arrange future clinical trials of these drugs, and to assess their effects, there is an urgent need for increased understanding of the natural course of both cardiac and nervous system disease caused by amyloid.
What the study involves for patients
Patients will undergo all the standard assessments that are usually performed at the NAC. There are no additional tests performed on patients (it is an observational study); the important difference is that we will systematically and carefully record all data in a special database for analysis. These include:
- Baseline assessment evaluation of the medical history, neurological and cardiac assessment, physical examination, blood tests, specialised cardiac imaging tests, functional tests and QOL assessment.
- Ongoing assessments include recording hospital admissions and changes in drug dosages. A member of the NAC study team will conduct a telephone consultation with any patient who has been admitted to their local hospital.
- Annual review at the NAC including weight, blood tests, specialised cardiac imaging (echocardiography and cardiac MRI scan), functional tests such as 6 minute walking distance and performance status assessment, neuropathy scoring (where relevant), and QOL assessment.
All of these assessments are routinely undertaken at the NAC as part of standard clinical care.
Who can take part in the trial
All patients diagnosed with ATTR amyloidosis assessed at the NAC are eligible for the trial if they are capable of providing written, informed consent..
Study aims
The TRANSCEND study aims to do for ATTR amyloidosis what the ALchemy study has done for AL amyloidosis.
The ALchemy study, which has been running since 2009, follows all patients diagnosed with systemic AL amyloidosis at the NAC. The data gathered has contributed greatly to our knowledge and understanding of the full spectrum of this disease in the UK. Some of our standard clinical management protocols have been adjusted in the light of the information gathered in this study.
The TRANSCEND study aims to achieve similar goals for ATTR amyloidosis by following all patients diagnosed with this condition at the NAC. It is a prospective study, which means that patients will be followed from the time of diagnosis. It is observational, meaning that there are no additional interventions for patients and the goal is systematic and careful data collection.
As discussed above, there have not previously been large scale trials following patients with all types of ATTR amyloidosis. Our understanding of the condition is rapidly evolving, with a significant recent increase in the frequency with which ‘wild-type’ ATTR amyloidosis is diagnosed. The only way we can fill in the gaps in our knowledge of this condition is by carefully following large numbers of patients over time.
The study itself will not involve any alterations in standard clinical practice. However, it is likely that understanding gained from this study may eventually influence and improve clinical management of patients.
Timing
The TRANSCEND study is ongoing.
The Eidos AG10-301 study (ATTRIBUTE-CM)
AG10 is a new selective TTR stabiliser drug being developed to treat ATTR amyloidosis. Destabilisation, misfolding and aggregation of TTR leads to ATTR amyloid tissue deposits. Several small molecules have been shown to bind to and stabilise TTR, potentially preventing the initiating event in ATTR amyloidogenesis. AG10 is a highly selective, potent TTR stabiliser hoped to halt or slow ATTR disease progression.
The trial
This is a phase 3 randomised international study of the efficacy and safety of AG-10 in patients with symptomatic ATTR amyloidosis affecting the heart. The study includes patients with hereditary ATTR amyloidosis and patients with wild type ATTR amyloidosis. Recruitment is now complete.
What the study involves for patients
Eligible patients were randomised in a 2:1 ratio to receive AG10 or matching placebo twice a day. Treatment will continue for a duration of about 32 months, including up to 35 days for screening, 30 months for treatment and up to 1 month for follow up. At the end of 12 months of treatment, treatment efficacy will be assessed using the 6 minute walk test and standardised questionnaires to evaluate health-related quality of life. At the end of 30 months treatment efficacy will be further assessed by analysis of all-cause mortality and frequency of hospitalisation related to cardiac causes. All patients completing the trial may be eligible for participation in an open label extension study of long term AG10 treatment.
Who can take part in the trial
Patients diagnosed with either hereditary ATTR amyloidosis or wild-type ATTR amyloidosis affecting the heart were eligible to participate in the trial.
For a full list of exclusion criteria, see the www.clinicaltrials.gov website.
Outcomes
The primary outcomes assessed will be:
- 6 minute walk test: Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes.
- Total number of deaths due to all causes and frequency of cardiovascular-related hospitalisation over 30 months.
Other outcomes assessed will include:
- Scores on standardised health-related quality of life questionnaires (Kansas City Cardiomyopathy Questionnaire (KCCQ)) at month 12 and month 30.
- Incidence of adverse events related to treatment.
- Pharmacodynamics assessments of TTR stabilisation at various time points.
- Effect of AG10 on cardiac biomarkers.
- AG10 activity across various TTR mutations.
Timing
This study has completed recruitment and is ongoing at the NAC. The NAC is the top recruiter globally.
The HELIOS-A study
Vutrisiran (ALN-TTRSC02) is a second generation RNA inhibitor TTR lowering drug, administered by subcutaneous injection. This trial will compare vutrisiran with patisiran, a first generation RNA inhibitor TTR lowering drug, which is administered by intravenous infusion.
The trial
This is a phase 3, randomised, open-label study to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in patients with hereditary transthyretin amyloidosis (hATTR amyloidosis) and neuropathy.
What the study involves for patients
Participants will receive vutrisiran or the reference comparator patisiran during the treatment period. The treatment period is followed by a treatment extension period during which all participants in the patisiran group will switch to vutrisiran.
Who can take part in the trial
Patients diagnosed with hereditary ATTR amyloidosis with neuropathy were eligible to participate in the trial
For a full list of inclusion and exclusion criteria, see the www.clinicaltrials.gov website.
Outcomes
The primary outcomes assessed will be:
- Change from baseline to Month 9 of treatment in the modified neurologic impairment score +7 (mNIS+7).
- Change from baseline to Month 9 of treatment in the Norfolk quality of life-diabetic neuropathy (Norfolk QoL-DN) Total Score.
Other outcomes assessed will include:
- Change from baseline in the timed 10 metre walk test at Months 9 and 18.
- Change from baseline in the modified body mass index (mBMI) at Months 9 and 18.
- Change from baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Months 9 and 18.
- Percentage reduction in serum transthyretin (TTR) levels at Months 9 and 18.
- Frequency of all-cause deaths and/or all-cause hospitalisations up to Month 18.
- Frequency of all-cause deaths and/or all-cause hospitalisations in participants with cardiac involvement up to Month 18.
Timing
This study has completed recruitment and is ongoing at the NAC. Overall 164 participants from around the world have been enrolled.
The HELIOS-B study
Vutrisiran (ALN-TTRSC02) is a second generation RNA inhibitor TTR lowering drug, administered by subcutaneous injection. This trial will compare vutrisiran with placebo in patients with ATTR amyloidosis with cardiomyopathy.
The trial
This is a phase 3, randomised, double-blind, placebo-controlled international study to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in patients with ATTR amyloidosis with cardiomyopathy.
What the study involves for patients
Participants will receive vutrisiran or placebo every 3 months over a period of 30-36 Months.
Who can take part in the trial
Patients diagnosed with either hereditary (hATTR) ATTR amyloidosis with cardiomyopathy, or wild-type (wtATTR) ATTR amyloidosis with cardiomyopathy,
For a full list of inclusion and exclusion criteria, see the www.clinicaltrials.gov website.
Outcomes
The primary outcome assessed will be:
- Composite endpoint of all-cause mortality and recurrent cardiovascular (CV) events.
Other outcomes assessed will include:
- Change from baseline in the 6 minute walk test at month 30.
- Change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) at Month 30.
- Change from baseline in mean left ventricular (LV) wall thickness by echocardiographic assessment at Month 30.
- Change from baseline in global longitudinal strain by echocardiographic assessment at Month 30.
- Composite endpoint of all-cause mortality and recurrent all-cause hospitalisations and urgent HF visits.
- All-cause mortality.
- Rate of recurrent CV events (CV hospitalisations and urgent HF visits).
- Change from baseline in N-terminal prohormone B-type natriuretic peptide (NTproBNP) at month 30.
Timing
This study has completed recruitment and is ongoing at the NAC. Overall 655 participants from around the world were enrolled including 151 NAC patients.
Patisiran in patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) disease progression post-liver transplant
Patisiran is an RNA inhibitor TTR lowering drug, belonging to the small interfering RNA drug class. It is administered by intravenous infusion. Patisiran has been shown to reverse neuropathy in patients with hereditary ATTR amyloidosis and neuropathy, and is approved by the regulatory authorities for this indication. This study will evaluate the efficacy and safety of patisiran in participants with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with disease progression after liver transplant.
What the study involves for patients
The study aims to enrol 20 participants to receive patisiran by intravenous infusion over a 12 month period.
Who can take part in the trial
Patients who received a liver transplant for treatment of hereditary ATTR amyloidosis at least 12 months before the study started, and who have an increase in polyneuropathy (PND) score after transplant may take part. Participants must have received stable immunosuppression treatment with prednisone for at least 3 months prior to starting the study. Patients may not take part in the study if they have previously received patisiran or inotersen, have clinically significant liver function test abnormalities, portal hypertension with ascites, severe renal failure, leptomeningeal amyloidosis or very poor performance status. For a full list of inclusion and exclusion criteria, see the www.clinicaltrials.gov website.
Outcomes
The primary outcome assessed wil be:
- Average Month 6 and Month 12 percentage reduction from baseline in serum transthyretin (TTR).
Other outcomes assessed will include:
- Change from baseline to Month 12 of treatment in the modified neurologic impairment score +7 (mNIS+7).
- Change from baseline to month 12 of treatment in the Norfolk quality of life-diabetic neuropathy (Norfolk QoL-DN) total score.
- Change from baseline in the Rasch-Built Overall Disability Scale (R-ODS) at month 12.
- Change from baseline in the composite autonomic symptom score (COMPASS-31) at month 12.
- Change from baseline in the modified body mass index (mBMI) at month 12.
- Percentage of participants with adverse events.
Timing
This study has completed recruitment and is ongoing at the NAC. Overall 24 participants from around the world were enrolled.
APOLLO-B: a study to evaluate patisiran in patients with transthyretin amyloidosis with cardiomyopathy (ATTR amyloidosis with cardiomyopathy)
Patisiran is an RNA inhibitor TTR lowering drug, belonging to the small interfering RNA drug class. It is administered by intravenous infusion. Patisiran has been shown to reverse neuropathy in patients with hereditary ATTR amyloidosis and neuropathy, and is approved by the regulatory authorities for this indication. This is a phase 3 randomised, double-blind, placebo-controlled multicentre study to evaluate the efficacy and safety of patisiran in patients with ATTR amyloidosis with cardiomyopathy.
What the study involves for patients
The study aims to enrol about 300 patients with ATTR amyloidosis (hereditary or wild-type). There will be an initial screening period of up to 45 days, a 12 month double-blind, placebo-controlled period (during which half the patients will receive patisiran and half will receive placebo, via intravenous infusion every three weeks), a 12 month open-label extension period (during which all patients will receive patisiran) and a 28 day follow-up period. The efficacy of patisiran treatment versus placebo will be assessed by evaluating changes from baseline in the 6 minute walk test and in a standardised cardiomyopathy symptom questionnaire at various time points.
Who can take part in the trial
Patients with ATTR amyloidosis affecting the heart (cardiomyopathy) were eligible to participate in the trial. For a full list of inclusion and exclusion criteria, see the www.clinicaltrials.gov website.
Outcomes
The primary outcome assessed will be:
- Change from baseline in 6 minute walk test at Month 12.
Other outcomes assessed will include:
- Change from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score at month 12.
- Composite endpoint of all-cause mortality, frequency of cardiovascular (CV)-related hospitalisations and change from baseline in 6 minute walk test over the 12 month double-blind period.
- Composite endpoint of all-cause mortality and frequency of all-cause hospitalisations over the 12 month double-blind period.
Timing
This study has completed recruitment and is ongoing at the NAC. Overall 360 participants rom around the wolrd were enrolled including 55 NAC patients.
CARDIO-TTRansform: a study to evaluate the efficacy and safety of AKCEA-TTR-LRx in participants with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM)
AKCEA-TTR-LRx is an RNA inhibitor TTR lowering drug, belonging to the antisense oligonucleotide drug class. This type of drug inhibits the production of the TTR protein. It is administered by subcutaneous injection.
The trial
This is a phase 3 global, double-blind, randomised study to evaluate the efficacy and safety of AKCEA-TTR-LRx compared to placebo in patients with ATTR cardiomyopathy (ATTR-CM).
What the study involves for patients
Participants will receive AKCEA-TTR-LRx or placebo by subcutaneous injection every 4 weeks for 120 weeks. All participants will also receive vitamin A supplements.
Who can take part in the trial
Patients diagnosed with ATTR cardiomyopathy may take part.
Patients may not take part in the study if they have cardiomyopathy not primarily caused by ATTR-CM, AL amyloidosis, prior liver or heart transplant, current or previous treatment with another RNA inhibitor drug.
For a full list of inclusion and exclusion criteria, see the www.clinicaltrials.gov website.
Recruitment of over 1000 participants is planned.
Study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001 in patients with with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and ATTR amyloid cardiomyopathy (ATTR-CM)
NTLA-2001 is an experimental therapy that could potentially be the first curative treatment for ATTR amyloidosis. CRISPR/cas9 technology is a novel gene editing tool that allows scientists to alter genes very precisely and efficiently. The protein Cas9 (or CRISPR- associated) is an enzyme that functions like a pair of molecular scissors, so that specific sections of the DNA can be removed, altered or added. NTLA-2001 is the first CRISPR therapy to be administered systemically (intravenously) to edit genes inside the body. Almost all the TTR in the body is made in the liver; NTLA-2001 uses a lipid nanoparticle delivery system to deliver the gene editing CRISPR protein to the liver. The goal is to permanently delete the gene for TTR in a single course of treatment. If this process happens in enough cells, it may lead to a potentially significant decrease in TTR protein production and thus, an impact on disease. Preclinical data has shown promising results, and this trial is the first time the therapy has been administered to humans.
The trial
This is a phase 1, first in human (FIH), open-label trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of NTLA-2001 in patients with hereditary ATTR amyloidosis with polyneuropathy and patients with ATTR amyloidosis and cardiomyopathy.
What the study involves for patients
In part 1 of the study, participants will receive a single dose of NTLA-2001 and then be followed for up to 24 months. In part 2, participants will receive the optimal biologically active dose (OBD) identified in part 1 as a single dose and then be followed for up to 24 months.
Who can take part in the trial
Patients diagnosed with hereditary ATTR amyloidosis and polyneuropathy or ATTR amyloid cardiomyopathy may take part. Patients may not take part in the study if they have non-ATTR amyloidosis, leptomeningeal TTR amyloidosis, or have used a different TTR-directed therapy for ATTR amyloidosis within a certain prior timeframe.
For a full list of inclusion and exclusion criteria, see the www.clinicaltrials.gov website. Recruitment of about 38 participants is planned.
Recruitment of 38 participants is planned.
Outcomes
The primary outcomes assessed will include pharmacokinetic and pharmacodynamic parameters reflecting efficacy of the therapy and adverse events.
Other outcomes assessed will include clinical assessments of polyneuropathy-related symptoms and cardiomyopathy.
Timing
This study is open for recruitment at the NAC
Cardiac amyloidosis trial
Background
Patients with cardiac amyloidosis (mostly due to AL or ATTR amyloidosis, occasionally related to other types of amyloidosis) often experience symptoms of angina (chest tightness or breathlessness on exertion). The mechanisms whereby amyloidosis causes these symptoms are not fully understood. We often use cardiac MRI to investigate patients with symptoms suggestive of angina to assess the blood flow (perfusion) to the heart muscle. Where abnormalities in blood flow are detected, patients are usually referred for coronary angiography for further assessment.
We are recruiting patients with cardiac amyloidosis and evidence of abnormal perfusion on cardiac MRI to undergo further assessment of heart blood flow at the time of coronary angiography. This will help us understand how amyloidosis affects blood flow to the heart muscle and we hope in the future we may be able to develop treatments to target this.