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Clinical Research at the National Amyloidosis Centre

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.

Examples of ongoing prospective studies at the NAC include:

  • The REVEAL study – a randomised phase 2 prospective trial of bortezomib combination chemotherapy in patients with advanced stage disease.  Patients are randomly assigned to receive either bortezomib-dexamethasone or cyclophosphamide.  Patient data is then collected over time, to compare the outcomes with the two treatment regimes.
  • The ALN-TTRSC in ATTR cardiac amyloidosis is an open label phase 2 prospective trial.  Patients with ATTR cardiac amyloidosis will receive a series of injections of a drug that is in relatively early stages of development, called ALN-TTRSC.  They will then be followed to assess the safety and tolerability of the drug.
  • ISIS TTR Rx.  The purpose of the trial is to determine whether ISIS TTR Rx can slow or stop the nerve damage caused by ATTR deposits in patients with familial amyloid polyneuropathy (FAP).   This study will enrol late Stage 1 and early Stage 2 FAP patients.   Patients will receive either ISIS TTR Rx or placebo for 65 weeks. This is a randomised controlled double blind phase 3 trial.

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.

At present there are no on-going retrospective studies at the NAC.

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 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 open for recruitment at the NAC, Oxford, Birmingham and Manchester.

EMN 03

The trial
This is an international randomised multi-centre phase 3 trial comparing oral melphalan-dexamethasone with bortezomib-melphalan-dexamethasone for patients with newly diagnosed early stage (stage 1 and 2) AL amyloidosis.

Brief background on advanced stage AL amyloidosis
Advanced stage cardiac AL amyloidosis is also called stage 2 or stage 3 amyloidosis.  Disease stage is determined according to the results of two specific blood tests called cardiac biomarkers:

  • brain-type natriuretic peptide (BNP), and
  • cardiac troponin T (TnT).

The concentrations of these two biomarkers are low at the time of diagnosis in patients with early stage disease.  High concentrations of these two biomarkers at the time of diagnosis are associated with significant amyloid deposits affecting the heart, and more advanced disease.  In stage 1 cardiac AL amyloidosis, the concentrations of both biomarkers are low.  In stage 2 cardiac AL amyloidosis, the concentrations of one of the biomarkers is increased, but not the other.  In stage 3 cardiac AL amyloidosis, the concentrations of both of the biomarkers are increased. Recently, an additional measure has also been used to help determine the disease stage:

  • dFLC (differential free light chains).  This test analyses the difference between concentrations of amyloidogenic free light chains and non-amyloidogenic free light chains.

What the trial involves for patients
In order to assess the effects of the two different chemotherapy regimes in patients with early stage cardiac AL amyloidosis, each patient taking part in the trial is randomly assigned to one of the following two treatment regimes:

  • MDex: Administration of oral melphalan (M) at 0.22 mg/kg and dexamethasone (Dex) at 40 mg daily for 4 consecutive days every 28 days (MDex) until end of therapy.
  • BMDex: Cycles 1 and 2 = MDex with bortezomib (B) at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle, cycles 3 to 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle.

Who can take part in the trial
Untreated patients diagnosed with stage 1 or 2 cardiac AL amyloidosis who are not candidates for stem cell transplantation are eligible for participation in this trial.

Outcomes
The primary outcome assessed will be the number of patients with complete response (CR) and partial response (PR) to treatment.  Other outcomes assessed (secondary outcomes) will include:

  • Complete haematologic response rate after 3 cycles and after completion of therapy.
  • Haematologic response rate at completion of therapy.
  • Organ response rates at 3, 6, 9 and 12 months.
  • Treatment-related mortality.
  • Toxicity.
  • Overall and progression-free survival.
  • Time to haematologic and organ response.
  • Quality of life.

Timing
This study is open for recruitment.

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 open for recruitment at the NAC.

The vital amyloidosis study

The trial
This is an international randomised phase 3 efficacy and safety trial of a new drug – NEOD001, in patients with newly diagnosed AL amyloidosis.  NEOD001 is a monoclonal antibody developed for the treatment of AL amyloidosis.  NEOD001 was granted orphan drug designation by the European Medicines Agency in 2013 and by the FDA in 2012.

What the trial involves for patients
In order to compare the effects of NEOD001 to the effects of placebo, each patient taking part in the trial is randomly assigned to one of the following two groups:

  • Experimental (NEOD001): Patients will receive NEOD001 (24 mg/kg, maximum dose of 2500 mg) as a 60-120 minute intravenous infusion once every 28 days.
  • Placebo: Patients will receive intravenous infusion of normal saline once every 28 days.

All patients will also receive standard chemotherapy as selected by their doctor.  First line chemotherapy must be a proteasome inhibitor containing regimen, with the proteasome inhibitor administered weekly.  Subsequent chemotherapy regimens may be prescribed at the doctor’s discretion.

Who can take part in the trial
Patients with newly diagnosed, treatment naïve, systemic AL amyloidosis affecting the heart, for whom the planned first line chemotherapy regimen contains a proteasome inhibiting agent administered weekly.  Patients with multiple myeloma and patients in whom autologous stem cell transplantation is planned are not eligible to take part in this trial.

Outcomes
The primary outcome assessed in this trial will be overall survival and hospitalisations because of heart disease.
Other outcomes assessed (secondary outcomes) from baseline to 9 months will include:

  • NT-proBNP best response.
  • Change in 6 minute walk test.
  • Change in scores on standardised questionnaires assessing general health and cardiomyopathy.
  • Renal and hepatic functions.

Timing
This study is open for recruitment at the NAC.

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.  Normal TTR can form amyloid fibrils in elderly people and there are many genetically variant types of TTR, which form amyloid much more aggressively and at an earlier age.  There are three distinct different types of ATTR amyloidosis:

  1. Familial amyloid polyneuropathy (FAP): hereditary - runs in families.
  2. Inherited amyloid cardiomyopathy: hereditary - runs in families.
  3. Senile systemic amyloidosis: not hereditary - does not run in families.

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 consisting of abnormal 'variant' TTR may cause:

  1. Familial amyloid polyneuropathy (FAP) is by far the most common form of hereditary amyloidosis.  This disease affects the nervous system, often also the heart and sometimes the kidneys, eyes and other organs.  Disease symptoms usually appear between the third and seventh decade, although they may start as early as age 20 or as late as age 80.   It is very rare, and the commonest type, associated with the Val30Met mutation, is thought to affect about 10,000 people in the whole world.  In the UK, FAP is most common in people of Irish ancestry, carrying the so-called Thr60Ala mutation.  FAP is inherited by autosomal dominant inheritance, meaning that each child of a person with FAP has a 50% chance of inheriting the abnormal gene.  Liver transplantation was introduced as ‘surgical gene therapy’ for FAP in 1991, in a collaboration between Swedish colleagues and our team.  Replacement of the patient’s own liver, producing the amyloidogenic variant of TTR, with a normal liver producing only normal TTR was intended to halt amyloid formation.  More than 2000 patients with FAP, most of whom carry the Val30Met mutation, have undergone liver transplantation, and it can lead to prolonged survival, especially in patients who receive their transplant early in the course of disease.  However, since normal TTR is also itself amyloidogenic, the disease often progresses in many liver transplant recipients.
  2. Inherited amyloid cardiomyopathy (heart disease), presenting in young adults is an extremely rare hereditary condition in which genetically variant TTR amyloid principally or exclusively affects the heart.  However amyloid cardiomyopathy in elderly black people, most commonly men over age 60, of West African ancestry, is caused by a particular TTR variant (Val122Ile) which is present in a significant proportion of individuals of this genetic background.  Because the genetic variant is so common, it is known as a polymorphism rather than a mutation.   Other organs are not affected and there is very rarely a family history due to the late age of onset and the fact that not all carriers of the affected gene actually get the disease.  This condition has only been recognised in recent years, was previously rarely diagnosed and is probably much more common than formerly realised.

Non-hereditary ATTR amyloidosis - 'wild-type' ATTR amyloid deposits

  1. Normal, 'wild-type' TTR may also be amyloidogenic, causing senile systemic amyloidosis:  Microscopic deposits of ‘wild-type’ ATTR amyloid are very common in the elderly, and have been found in 1 in 4 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 is called 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 in some people.  Senile systemic 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 before age 60.

Drugs for ATTR amyloidosis

There are no available drug therapies for ATTR amyloidosis in the UK.  However, several drugs are in varying stages of development and licensing.  See below for details of ongoing studies and studies about to begin at the NAC.

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.

ATTR amyloidosis is caused by amyloid deposits made up of a protein called transthyretin (TTR).  There are three distinct different types of ATTR amyloidosis:

  1. Familial amyloid polyneuropathy (FAP): hereditary - runs in families.
  2. Inherited amyloid cardiomyopathy: hereditary - runs in families.
  3. Senile systemic amyloidosis: not hereditary - does not run in families.

The TRANSCEND study will include patients seen at the NAC with all three types of ATTR amyloidosis.

ATTR amyloidosis: filling in the gaps in our knowledge
FAP
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 FAP and to determine the optimal time for liver transplantation.  Most patients who have undergone liver transplantation carry the Val30Met mutation.  However, there is a lack of data on the natural history of non Val30Met associated FAP, as most of these patients have not undergone liver transplantation and have not previously been consistently followed in large numbers.  Liver transplantation for FAP does not prevent continued build-up of ATTR amyloid in the heart.  Sometimes the ‘wild type’ TTR produced by the transplanted normal liver may deposit ‘on top of’ the ‘variant’ ATTR template already present in the heart.  There is a need for careful cardiac follow up of patients who have undergone liver transplantation for FAP, to enhance our understanding of this process.

Senile systemic amyloidosis and amyloid cardiomyopathy
Newly available cardiac imaging techniques (cardiac magnetic resonance imaging and DPD scintigraphy) have resulted in greatly increased diagnosis of cardiac TTR amyloidosis.  There has been a 40 fold increase in the number of referrals of patients to the NAC with senile ATTR amyloidosis over the past decade.  ATTR amyloidosis may be a 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.

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 be useful for 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 disease.

What the study involves for patients
Patients will undergo all the standard assessments that are usually performed at the NAC. The only difference is that we will record all data in a special database for analysis.  These include:

  1. Baseline assessment: evaluation of the medical history, neurological and cardiac assessment, physical examination, blood tests, specialised cardiac imaging tests and QOL assessment.
  2. On-going assessments including posting a monthly Clinical Progress Form to the NAC, detailing any changes in the medical condition, patient’s weight or treatment.  If there are marked changes then a member of the NAC study team will conduct a telephone consultation with the patient.
  3. Six monthly review at the NAC including weight, blood tests, echocardiography and functional tests such as 6 minute walking distance and performance status assessment.
  4. Twelve monthly review including additional assessments such as neuropathy scoring, specialised cardiac imaging, QOL assessment and patient satisfaction survey.

Who can take part in the study
All patients diagnosed with ATTR amyloidosis assessed at the NAC are eligible for the study 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 also observational, meaning that the goal is data collection.

As discussed above, there have not previously been large scale studies 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 senile cardiac 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 possible that understanding gained from this study may eventually influence clinical management of patients.

Timing
The TRANSCEND study is due to open in 2015 at the NAC but many of the assessments are already being routinely carried out.

Efficacy and safety of ISIS-TTR Rx in familial amyloid polyneuropathy

ISIS TTR Rx is one of a class of drugs called antisense oligonucleotides which act by a type of gene therapy known as ‘gene silencing’.  The drug is not intended to repair the faulty TTR gene, rather to ‘silence’ its effects by interfering with TTR production in the liver cells.  All proteins in the body are produced in cells by a process called ‘gene expression,’ using the information present in the genetic code.  This process can be likened to the building of a house.  The DNA making up the genes in the nucleus of each cell are like the architect’s blueprints.  Other molecules in the nucleus of the cell, known as messenger RNA (mRNA) and transfer RNA (tRNA) act like the various builders, electricians, plumbers, etc, who need to read and follow the blueprints and communicate effectively together to ensure that the end product is a success.  In the early steps of protein production, the information contained in the DNA in the cell’s nucleus is conveyed out of the nucleus by messenger RNA.  The messenger RNA contains the instructions for protein structure which are then translated from the language of genetic code into the language of amino acids, the building blocks of proteins.

Clin Res Fig 1

The ISIS TTR Rx molecule is made up of a short string of nucleotides (the building blocks of the genetic code in DNA and RNA) designed to bind tightly to TTR messenger RNA.  When this binding occurs, the TTR messenger RNA is broken down by an enzyme in the cell, preventing the translation step in protein building and thus blocking the production of both ‘variant’ TTR and normal ‘wild type’ TTR protein.  It is hoped that decreasing the amount of TTR protein in the blood will reduce the formation of ATTR amyloid deposits, slowing or halting disease progression.  After liver transplantation, wild type TTR from the new liver may continue to deposit as amyloid fibrils.  However, because ISIS TTR Rx is hoped to reduce the production of both variant and wild type TTR, if successful, this approach may be more effective than liver transplantation in halting amyloid deposit progression.

The trial
The purpose of the trial is to determine whether ISIS TTR Rx can slow or stop the nerve damage caused by ATTR deposits in patients with FAP.  This study will enrol FAP patients with early stage neuropathy.  Patients will receive either ISIS TTR Rx or placebo for 65 weeks.  This is a randomised controlled double blind phase 3 trial.  Phase 1 trials in small numbers of people have already established that the drug is safe in humans, have determined an appropriate dosage range, and identified side effects.  Phase 3 trials involve a large number of patients.  The trial is multicentre meaning that patients all around the world are taking part in this trial.

What the trial involves for patients
In order to see whether ISIS TTR Rx helps patients with FAP, each patient taking part in the trial will be randomly assigned to one of 2 groups:

  • Intervention group - these patients will receive 300 mg of the ISIS TTR Rx drug by subcutaneous injection 3 times on alternate days in the first week, then once weekly for 64 weeks.
  • Control group - these patients will receive placebo (dummy injection) by subcutaneous injection 3 times on alternate days in the first week, then once weekly for 64 weeks.

This is a double blind trial.  This means that the doctors and nurses running the trial at the NAC, and the patients participating will not know which patients are receiving ISIS TTR Rx and which are receiving placebo.

Who can take part in the trial
Patients with stage 1 and stage 2 FAP, aged between 18 to 75 years who can walk unaided or with no more than one stick/cane are eligible to take part.

Patients who have undergone liver transplantation or have other serious diseases are not eligible to take part.  For a full list of exclusion criteria, see the www.clinicaltrials.gov website.

Outcomes
This trial is only designed to assess the effects of ISIS TTR Rx on neuropathy caused by FAP, not on heart disease.

The main (primary) outcome measures will be change in baseline score in two standardised measures for assessing the severity of neuropathy:

  1. The modified Neuropathy Impairment Score.
  2. The Norfolk Quality of Life Diabetic Neuropathy questionnaire (this was developed for patients with diabetic neuropathy and is applicable to FAP even though FAP has got nothing at all to do with diabetes).

All patients will undergo neuropathy assessment at the start of the trial, so that there will be a baseline score for comparison.  Measurement of the change from baseline in the TTR levels in the blood will be a secondary measure.

Timing
The trial started recruiting participants in other centres at the end of 2012.  Recruitment at the NAC is ongoing.

ALN-TTRSC in ATTR cardiac amyloidosis

ALN-TTRSC belongs to a class of drugs called small interfering RNA (siRNA) drugs which act by a type of gene therapy known as ‘gene silencing’.  The drug is not intended to repair the faulty TTR gene, rather to ‘silence’ its effects by interfering with TTR production in the liver cells.  All proteins in the body are produced in cells by a process called ‘gene expression,’ using the information present in the genetic code.  This process can be likened to the building of a house.  The DNA making up the genes in the nucleus of each cell are like the architect’s blueprints.  Other molecules in the nucleus of the cell, known as messenger RNA (mRNA) and transfer RNA (tRNA) act like the various builders, electricians, plumbers etc who need to read and follow the blueprints and communicate effectively together to ensure that the end product is a success.  In the early steps of protein production, the information contained in the DNA in the cell’s nucleus is conveyed out of the nucleus by messenger RNA.  The messenger RNA contains the instructions for protein structure which are then translated from the language of genetic code into the language of amino acids, the building blocks of proteins.

Clin Res Fig 2

The ALN-TTRSC molecule is made up of a short string of nucleotides (the building blocks of the genetic code in DNA and RNA) designed to bind tightly to TTR messenger RNA.  When this binding occurs, the TTR messenger RNA is broken down by an enzyme in the cell, preventing the translation step in protein building and thus blocking the production of both ‘variant’ TTR and normal ‘wild type’ TTR protein.  It is hoped that decreasing the amount of TTR protein in the blood will reduce the formation of ATTR amyloid deposits, slowing or halting disease progression.  After liver transplantation, wild type TTR from the new liver may continue to deposit as amyloid fibrils.  However, because ALN-TTRSC is hoped to reduce the production of both variant and wild type TTR, if successful, this approach may be more effective than liver transplantation in halting amyloid deposit progression.

The trial
This is a multi-centre, open-label, multi-dose phase 2 trial.  Phase 2 trials are performed at a relatively early stage in drug development, and the trial aims to recruit only 12 patients.  The trial is multicentre meaning that patients and researchers from different sites (in the UK and the US) are taking part.  The trial is open-label, meaning that all patients and researchers know the drug and the dose being give.  It is not placebo controlled, meaning that none of the participants will receive a dummy (placebo) injection.

What the trial involves for patients
Each patient taking part in the trial will receive 10 subcutaneous injections of ALN-TTRSC on an outpatient basis.  In the first week there will be 5 daily doses on days 0, 1, 2, 3 and 4.  After that there will be 5 weekly doses.  There will be clinic visits for screening up to 28 days before drug administration, and more visits for follow up up to 90 days after starting participation in the trial.

Who can take part in the trial
Patients with biopsy proven TTR cardiac amyloidosis, aged between 18 to 80 years who are clinically stable are eligible to take part.  For a full list of exclusion criteria, see the www.clinicaltrials.gov website.

Objectives
The purpose of the trial is to evaluate the safety and tolerability of multiple doses of ALN-TTRSC in patients with TTR cardiac amyloidosis.  The trial does not aim to assess the effects of ALN-TTRSC on the patients’ clinical condition. If this trial finds that ALN-TTRSC is safe and well tolerated, then future, larger phase 3 trials may evaluate the clinical efficacy of this drug.

Timing
Recruitment at the NAC started in December 2013 and is ongoing.

Trial for AA amyloidosis

The trial
This is an international randomised multi-centre phase 3 trial looking at whether a novel agent, eprodisate, improves outcome in patients with moderate renal disease and proteinuria.

Brief background on AA amyloidosis
AA amyloidosis may complicate chronic infections or inflammatory diseases.  It is characterised by extracellular deposits of amyloid fibrils composed of fragments of serum amyloid A protein (SAA), an acute phase reactant protein.  The kidney is the most frequent organ involved, with protein leaking into the urine and renal impairment.  Reducing the level of circulating SAA by treating the underlying inflammatory condition is the current treatment but this is not always possible.  Eprodisate competes with molecules that encourage early amyloid fibril formation and an earlier clinical trial suggested that it may slow down progressive renal failure in patients with AA amyloidosis.  This study is designed to see if that can be confirmed in a larger group of patients.

What the trial involves for patients
In order to assess the effects of eprodisate in patients with AA amyloidosis, each patient taking part in the trial is randomly assigned to either:

  • Eprodisate:  tablets taken twice daily
  • Placebo:  tablets taken twice daily

Who can take part in the trial
Patients with confirmed AA amyloidosis with at least 1 g of proteinuria and without severe kidney damage (creatinine clearance greater than 20 ml/min).

Outcomes
The primary outcome assessed will be:

  • the number of patients whose kidney function gets worse by more than 40% or who reach end stage kidney failure

Other outcomes assessed (secondary outcomes) will include:

  • change in renal function and urinary protein leak over time
  • overall survival
  • side effects and safety

Timing
This study has been recruiting since 2011.