Amyloidosis Trials

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General background and terminology used in clinical trials

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)  trial 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 amyloidosis trials 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:

  1. 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
  1. 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
  • 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

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
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