When someone is affected by aHUS, the issue of it being a rare disease soon becomes apparent. The injustices felt by those with rare diseases permeate the thinking of those in society who are rare.
People identify with it when it comes to diagnosis, treatment, information and research. Small populations trying to get the attention that much bigger populations are more likely to be given. To be recognised as a group of concern. To no longer be an orphan that no one looks after.
Fortunately aHUS stopped being an orphan disease over a decade ago. The drug eculizumab did that. Translational research from its use for PNH to aHUS meant that the thrombotic microangiopathy identified as aHUS had a potential clinically effective treatment. It needed clinical trials for that to be confirmed.
Who would be included in such a trial and who would not be allowed to participate became important. In all likelihood many aHUS patients who were around at that time did not know there were such trials going on. The same may be true today about current aHUS trials. The patients depend on their treating clinicians to make them aware.
Clinical trials are well regulated. That was not always the case. Bad and unethical practices in the past by some of those involved, however well intended to improve societal health, have made it necessary for ethical principles and practices to be adopted and deployed. These resulted in processes and procedures that underpin all experiments on people today.
People have to be respected as individuals and any participation in a trial for a new drug must not risk causing harm. Participation has to be voluntary and any decision by the patient to be participate must be well informed.
An informed consent is a process by which a subject voluntarily confirms his or her willingness to participate in a particular
trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to
participate. Informed consent is documented by means of a written, signed and dated informed consent form.
No aHUS patient was involved in testing the safety of eculizumab. That was done by healthy volunteers who were paid to do it.
Patients do not get paid for trial participation but any costs arising from attending for tests etc. are covered . That is common practice. No aHUS patient was involved in testing levels of eculizumab needed either.
By the time aHUS patients had become involved in trials of eculizumab, PNH patients had gone through their trials. In their trials PNH patients had been split into two groups, one group receiving eculizumab and the other a placebo with patients not knowing which group they were in. That way a comparison could be made between both groups if, and how quickly the PNH patient “hemolysis” returns. If it does, patients can be reverted to conventional treatment which was a blood transfusion with little or no harm done.
The aHUS trial phase 2 was not done that way. The alternative treatment for aHUS patients who were in a medical emergency would have been on plasma exchange, and most likely they were already needing dialysis. It was also likely that plasma therapy was not effective or patients were sensitive to it . In 2009 the first trial of eculizumab was of 15 patients who swapped from plasma therapy to this complement inhibitor.
If it worked, receiving eculizumab could not only stop the haemolysis but could also allow kidneys to recover some function. With a placebo infused and no plasma exchange irreversible harm and even death could result. There would be no use of placebo in aHUS trials, all trialists would receive eculizumab and so no direct comparisons would be made. But there was plenty of evidence from the past on what would happen to aHUS patients. Likely mortality or chronic kidney failure.
So the scope of the first aHUS trials was to recruit 15 patients into the study and to be for adults only. Another adult trial was to follow in 2010 this time there were 44 adult participants. Trials for treatment of children would follow. Who could be involved in the first trial? That was determined by the trial’s inclusion / exclusion criteria.
To be included patients need to meet these criteria.
- Male or female patients’ ≥18 years of age who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS).
- Patients must be receiving PT ( plasma therapy) for aHUS and must be observed to receive ≥ 1 PT treatment every two weeks and no more than 3 PT treatments/week (at an unchanged frequency) for at least 8 weeks before first dose of IP.
- Platelet Count Pre-PT Baseline Set-Point (collected in the hours before the Qualifying PT Episode) is within 75% of the average of the Pre-PT platelet counts collected at Screening and during the Observation Period.
- Known complement regulatory protein genetic abnormality.
- Lactate dehydrogenase (LDH) level at screening or at the onset of the current aHUS episode was ≥ ULN. If LDH is normal at screening, other markers indicative of ongoing hemolysis such as haptoglobin, schistocytes should be evaluated and discussed with Sponsor.
- Creatinine level ≥ ULN for age.
- Female patients of childbearing potential must be practicing an effective, reliable and medically approved contraceptive regimen during the entire duration of the study, including the follow-up period and for up to 5 months following eculizumab treatment discontinuation.
- Able to give written informed consent.
- Able and willing to comply with study procedure
Most are clinical eligibility conditions but notably condition 4 limits participation to those who are known to have a genetic susceptibility. Something rarely known at the time of an aHUS onset. That was not a requirement for the 2010 trial a diagnosis of aHUS was enough, thereby giving trial access to those who could not be genetically tested.
Condition 7 meant female patients could not get pregnant when participating in the study.
Those patients already pregnant would also be excluded according to the exclusion criteria condition 11 (see below) . Neither could post-partum, the most common trigger period for female HUS patients ,women patients participate when lactating. These conditions are to prevent any unknown harm to the foetus, or newborn child. It would need evidence from real life case by case studies of aHUS mothers to help this large cohort of aHUS patients to benefit from treatment much later.
Note that ability to give informed consent is listed as criterion number 8. This was not an explicit inclusion criterion for the 2010 trial.
The exclusion criteria mostly try to limit treatment to patients with a complement mediated, or primary, form of aHUS and avoid anyone with other confounding conditions, other primary (TTP or HUS) or secondary TMAs. Transplant patients and those with anti factor H antibody aHUS were not excluded.
But aHUS dialysis patients who would need to have an unsupported transplant operation which may then trigger aHUS and would then need to have plasma therapy for at least two weeks to be eligible. A long shot!
- TTP, (defined as ADAMTS-13 activity <5%) from an historical observation (prior to initiation of plasma therapy) or as tested at the screening visit by the central laboratory.
- Malignancy within 5 years of screening.
- Typical HUS (Shiga toxin +).
- Known HIV infection.
- Identified drug exposure-related HUS.
- Infection-related HUS.
- HUS related to bone marrow transplant.
- HUS related to vitamin B12 deficiency.
- Patients with a confirmed diagnosis of sepsis.
- Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease.
- Pregnancy or lactation.
- Unresolved meningococcal disease.
- Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome.
- Any medical or psychological condition that, in the opinion of the investigator, could increase the patient’s risk by participating in the study or confound the outcome of the study.
- Patients who have received previous treatment with eculizumab.
- Patients receiving IVIg within 8 weeks or Rituximab therapy within 12 weeks of the screening visit.
- Patients receiving other immunosuppressive therapies such as steroids, mTOR inhibitors or tacrolimus are excluded unless:  part of an established post-transplant anti-rejection regime,  patient has confirmed anti-CFH antibody requiring immunosuppressive therapy, and  dose of such medications have been unchanged for at least 4 weeks prior to the screening period and throughout the Observation Period or  patient is experiencing an acute aHUS relapse immediately after transplant.
- Patients receiving Erythrocyte Stimulating Agents (ESAs) unless already on a stable dose for at least 4 weeks prior to the screening period, or a washout period of at least 2 weeks from the last dose of ESA therapy.
- Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedures beginning 4 weeks prior to screening and throughout the entire trial.
- Hypersensitivity to eculizumab, to murine proteins or to one of the excipients.
All medical trials need ethical approval from an ethics committee. It takes time to set up and start a trials and even more time to observe what happens to participating patients.
The aHUS eculizumab trial was successful and the primary endpoints were met and what followed as they say is history.
Article No. 537