Sunday, December 07, 2014

Testing Re-Purposed Medicines In the 2014 Ebola Outbreak


This paper relates specifically to the pharmaceutical response to the outbreak of Ebola Virus Disease (EVD) in West Africa. It advocates the use of drugs (some listed in the Appendix) that already have an established place in other fields of medicine, and that have been shown in animal studies to be effective in reducing the life-threatening “cytokine storm” associated with some infections, but that have not been through the normal process of human trials in EVD. These medications should be re-purposed for use in EVD, and their efficacy tested in simple field trials.
Education (“sensitisation”) about the way that EVD is transmitted is absolutely vital in prevention of spread, and re-hydration and correction of metabolic abnormalities rightly remain the mainstay of therapy in EVD. We must make sure that enough materials, skills and personnel are available to maintain these general supportive measures, but at the same time, we must look for medicines that can increase the recovery rate.

Treatment approaches

Rapid development of vaccines is a hopeful avenue of progress[i], but the limitation with vaccines is the lag between gathering evidence that they are effective, and producing sufficient doses to meet the need of the whole population. However, they certainly will have a role in protecting the very courageous medical and nursing staff.
“Convalescent Serum” - transfusions of serum from patients who have recovered from the infection is being tested[ii]. This approach has the clear advantage that the supply is provided by grateful recovered patients, and will therefore be more commensurate with the demand. It is promising, and is under development[iii], although preparation of safe, pure serum will be challenging and costly. If we can increase the recovery rate, more serum will become available.
Established anti-viral agents such as Brincidofovir are also being tested.
The World Health Organisation confirmed on 12th August in Geneva that the use of untested drugs on Ebola patients would be ethical[iv]. “On 11 August 2014, WHO convened an Ethics Panel to consider and assess the ethical implications of the potential use of unregistered interventions. The panel reached consensus that in the particular circumstances of this outbreak, and provided certain conditions are met, it is ethical to offer unproven interventions for which the safety and efficacy have not yet been demonstrated in humans as potential treatment or prevention… In addition, existing drugs approved for other conditions, which show good evidence of activity against Ebola in laboratory models, may be evaluated and ‘re-purposed’ for use, if efficacy is demonstrated.[v] Note that the only way of demonstrating efficacy is by trials in the field. However, the meeting decided to concentrate efforts on a small number of potential treatments, notably convalescent serum and vaccines, and there was no resolution to further explore the use of re-purposed drugs.
Meeting in Geneva on 4-5th September 2013[vi], WHO participants concluded “the highest therapeutic priority should be given to human convalescent serum, whole blood, and blood products. It was proposed that survivors of EVD should be followed up carefully, not only to determine the long-term effects of EVD, but also to identify potential donors of blood for therapeutic use. The next priority would be the promising vaccine candidates and potential therapeutics”. Perhaps regrettably, the use of re-purposed medicines was not prioritised at this meeting.
The reason given for this decision is that the challenges of field testing of any medical intervention are daunting. “For any study to be planned and then conducted, there is a need for a number of key players to be fully behind and aligned: manufacturers/developers, regulators both in the affected countries and other regions, WHO, MSF and other NGOs who are providing help locally[vii].
This decision suggests that organisational difficulties are inadvertently inhibiting chances of improvement in the medical treatment of a serious epidemic. Such difficulties can be overcome, given political will. If manufacturers, national health services and NGOs can agree, trials of re-purposed medicines, could go ahead. We should therefore consider how this roll-out could be designed.

Trials of re-purposed medicines

In a situation where patients are dying because there are not enough nurses to attend to them, a full research effort which stands a chance of being published in a peer-reviewed journal would be inappropriate and incongruous, since, unlike practical medicine and nursing in a developing world setting, research requires a full complement of staff and very high standards of control of the patient’s situation. However, the demands of perfection must not be allowed to stand in the way of medical progress.
To insist on classically perfect study conditions is to insist that very little research will be carried out during the present epidemic – or indeed, any epidemic of this magnitude. This would be irrational. It is highly likely that in coming years, medicine will encounter an epidemic with a comparable mortality rate to EBV, but with air-borne transmission, which would make it a far greater challenge. In this event, we will need all the help we can get, and it would be deeply regrettable if medicine is lacking inexpensive and effective ways of treating a disastrous epidemic simply because it is deemed that re-purposed medicines are not worth testing in the present outbreak. The West African Ebola epidemic presents us with an opportunity to learn about controlling the cytokine storm. We may find that it is impossible to do so with re-purposed drugs. Equally, we may discover that they are helpful additions to existing supportive treatments. 

Study design

The present proposal is that we should carry out a number of very simple tests for re-purposed drugs as follows:
1.        A research team approaches a field treatment centre and explains that if the staff wish to collaborate, they will be supplied with medications, some of which will be Preparation A and some Preparation B. One of them is a dummy, one is a drug that is used in other fields of medicine, that has demonstrated efficacy against fever in animals, but has not yet been tried out on humans. It is explained that there is no guarantee that the preparations will work to help patients with EBV, but that there is a chance that a new therapy for Ebola may be discovered by their work.
2.        If the treatment centre staff agree, a trial is commenced. The initial dose given will be a fraction of the smallest dose used for the medicine’s official indication, the dose to be decided by consideration of the drug’s known side effects.
3.        One or two research workers will join the treatment centre team to supervise delivery of medications, and to collect the data.
4.        The endpoint will be death or discharge from hospital. If possible, changes to the patient’s condition and possible side effects will be noted.
5.        If a statistically significant advantage emerges from the data, the code may be broken, and if improvement is associated with the active drug, the trial will be repeated at a higher dose.
6.        If there is no difference between the placebo and the active drug, the trial will again be repeated at a higher dose.

If any significant differences emerge between outcomes for placebo and trial drug in these pilots, more elaborate and extensive trials will be run.
Results from the various treatment centres will be collated and reviewed.

Appendix: Medications that can be re-purposed to treat EVD

Cytokine storm is an exaggerated reaction on the part of the cellular immune system. A positive feedback loop forms between cytokines released at the site of infection, which attract more defence cells, which produce more cytokines. It is this vicious circle that causes Ebola infection to have such high mortality. 
OX40 is a protein secreted by T-cells that keeps them from dying, and therefore perpetuates the feedback loop. OX40 IG is a synthetic immunoglobulin that neutralises this protein. It has been shown to be effective in mice[viii]. It was tested in 2003, but it seems that it was bought by a venture capital group that decided not to develop it.
Some of the drugs mentioned below act on cytokine storm, but others have other modes of action.
The following are some examples of drugs that can be re-purposed:
1.        Simvastatin and Gemfibrozil, both lipid-lowering drugs in common use, have been shown to have an effect in reducing the cytokine response. In the case of Simvastatin, an effect has been shown in humans, albeit not in acute infection. Simvastatin also has an effect on the replication of some viruses. It decreases OX40[ix].
Terblanche has produced an excellent review of the immunomodulatory and antiviral effects of statins[x].
2.        ACE Inhibitors and Angiotensin II receptor blockers are medications in common use against hypertension. The Renin-Angiotensin System (RAS) is involved in the cytokine storm[xi]. ACE is involved in pulmonary inflammation[xii],[xiii]. They have been shown to reduce the cytokine feedback loop[xiv]. Examples of ACE inhibitors are ramipril, perindopril and Lysinopril. Angiotensin II blockers: losartan, candesartan, valsartan. Care must be exercised in using these in Ebola, as their hypotensive effect may aggravate any hypotension present due to dehydration.
3.        TNF Blockers are medications routinely used in arthritis and other inflammatory conditions, and work by inhibiting Tumour Necrosis Factor (TNF) which is implicated in cytokine storm. Some are monoclonal antibodies (infliximab, adalimumab, certolizumab), and some are more simple compounds such as bupropion, in common use in smoking cessation.
4.        Naltrexone, a long established opioid receptor antagonist, may inhibit cytokine storm. There is evidence from animal studies[xv],[xvi],[xvii],[xviii] that shows it may be clinically effective. It is inexpensive.
5.        Selective estrogen receptor modulators (SERMs) such as clomiphene, commonly used in treatment of infertility and breast cancer, have been shown to inhibit the Zaire strain of Ebola Virus in vitro and in vivo, in mouse studies[xix].
6.        Ion channel blockers such as Amiodarone commonly used in treating hypertension, have been shown to have an effect on the entry of filoviruses into cells[xx].

Note that these medicines are already in use, and therefore have been tested for human acceptability, although not specifically in patients with fever. Their side effects and contra-indications are known. They are relatively inexpensive, and can easily be made available in quantities sufficient for initial trials.
It is self-evidently true that we do not know what happens when these drugs are used in patients infected with the Ebola virus, but the only way to find out in good time is to test them in the field. They may have adverse effects in the given situation, they may have no benefit whatsoever, but equally, one or more of them, alone or in combination, may prove helpful, and the exercise will then have been at least worthwhile, and even, possibly, game-changing.
In conclusion, there are several modalities of treatment for Ebola that must be tried in the present outbreak. Their deployment will be “off-licence” and their efficacy must be monitored, but to subject them to trial in the Ebola situation that we are currently engaged with is ethical and perfectly rational. It is hoped that the small initial pilot studies outlined in this paper will be rolled out as soon as possible.

Dr Richard Lawson MB BS, MRCPsych
North Somerset, UK
Sunday, 07 December 2014

[vii] Enrica Alteri MD, Head of Human Medicines Evaluation Division, European Medicines Agency, personal communication

[viii] Humphreys I R, Walzl G, Edwards L, Rae A, Hill S, Hussell T. A Critical Role for OX40 in T Cell-mediated Immunopathology during Lung Viral Infection. The Journal of Experimental Medicine 2003;198:1237-1242
[ix] Liu B, Yu G, Yang Z, Sun L, Song R, Liu F, et al. Simvastatin Reduces OX40 and OX40 Ligand Expression in Human Peripheral Blood Mononuclear Cells and in Patients with Atherosclerotic Cerebral Infarction. The Journal of International Medical Research. 2009;37:601-10.
[xi] Genctoy, G; B Altun et al. (February 2005). "TNF alpha-308 genotype and renin-angiotensin system in hemodialysis patients: an effect on inflammatory cytokine levels?". Artif Organs 29 (2): 174–178.
[xii] Marshall, RP; P Gohlke et al. (January 2004). "Angiotensin II and the fibroproliferative response to acute lung injury". Am J Physiol Lung Cell Mol Physiol (Royal Free and University College London Medical School) 286 (1): 156–164. PMID 12754187.
[xiii] Moldobaeva, A; EM Wagner (December 2003). "Angiotensin-converting enzyme activity in ovine bronchial vasculature". J Appl Physiol (Department of Medicine, Johns Hopkins University) 95 (6): 2278–2284.
[xiv] Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int. 2002;62(S82):S12-S22.
[xv] Peng X, Mosser DM, Adler M, et al. Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages, Journal of Leukocyte Biology. 2000;68:723-728.
[xvi] Hola N V, Zaji Cova A, Krulova M, Blahoutova V, Wilczek H. Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clinical & Experimental Immunology 2003;132:40-45.
[xvii] Lin S L, Lee Y M, Chang H Y, Cheng Y W and Yen M H. Effects of naltrexone on lipopolysaccharide-induced sepsis in rats. J Biomed Sci. 2005;12:431-40. 
[xviii] Greeneltch KM, Haudenschild CC, Keegan AD, Shi Y. The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production. Brain Behav Immun. 2004;18:476-84.

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