Health Professionals and COVID-19

[o_e_l_e_o]

Here are some of the old papers which I see being used as an evidence base for trying lopinavir/ritonavir against SARS-CoV-2, which all include ribavirin alongside lopinavir/ritonavir for SARS-CoV or MERS-CoV. As you say bitbollo, I'm not aware of any current trials using this regime against SARS-CoV-2.

Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004 Mar; 59(3): 252-6.
https://thorax.bmj.com/content/59/3/252.long

Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003 Dec; 9(6): 399-406.
https://www.hkmj.org/abstracts/v9n6/399.htm

Park SY, Lee JS, Son JS, Ko JH, Peck KR, Jung Y, et al. Post-exposure prophylaxis for Middle East respiratory syndrome in healthcare workers. J Hosp Infect. 2019 Jan; 101(1): 42-46.
https://www.journalofhospitalinfection.com/article/S0195-6701(18)30484-5/fulltext


I'd like to keep on topic about evidence based treatment options for SARS-CoV-2, and not about the politics surrounding pharmaceutical companies please. Many thanks.

[1713419372]

1713419372

[1713419372]

1713419372

[1713419372]

1713419372

[1713419372]

1713419372

[af_newbie]

Here are some of the old papers which I see being used as an evidence base for trying lopinavir/ritonavir against SARS-CoV-2, which all include ribavirin alongside lopinavir/ritonavir for SARS-CoV or MERS-CoV. As you say bitbollo, I'm not aware of any current trials using this regime against SARS-CoV-2.

Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004 Mar; 59(3): 252-6.
https://thorax.bmj.com/content/59/3/252.long

Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003 Dec; 9(6): 399-406.
https://www.hkmj.org/abstracts/v9n6/399.htm

Park SY, Lee JS, Son JS, Ko JH, Peck KR, Jung Y, et al. Post-exposure prophylaxis for Middle East respiratory syndrome in healthcare workers. J Hosp Infect. 2019 Jan; 101(1): 42-46.
https://www.journalofhospitalinfection.com/article/S0195-6701(18)30484-5/fulltext


I'd like to keep on topic about evidence based treatment options for SARS-CoV-2, and not about the politics surrounding pharmaceutical companies please. Many thanks.

https://www.fiercepharma.com/pharma-asia/does-abbvie-s-hiv-drug-kaletra-also-works-covid-19-maybe-not-nejm-study-finds

https://www.npr.org/sections/health-shots/2020/03/21/819099156/might-the-experimental-drug-remdesivir-work-against-covid-19

[bitbollo]

https://www.fiercepharma.com/pharma-asia/does-abbvie-s-hiv-drug-kaletra-also-works-covid-19-maybe-not-nejm-study-finds
.....

I have already posted this news from fiercepharma some days ago please find below also a short summary.

@o_e_l_e_o very useful and interesting topic! it's always a pleasure
[I am a registered pharmacy in Italy, working for a pharmaceutical company (Clinical trials)]

Please find below the last update regarding Kaletra (ALUVIA (r) trade name in EMEA) (originally posted in Italian board section: https://bitcointalk.org/index.php?topic=5231876.msg54065220#msg54065220 )

Kaletra (ALUVIA (r) trade name in EMEA)
It was unable to demonstrate any clinical improvement in the first clinical studies found for COVID-19 (compared to "standard of care").
Long story short:
The trial recruited 199 patients and began on January 18, 2020, when very little is known about this virus and associated clinical conditions.
It is not a complete defeat, at least for the moment.
Probably, some analysts point out, for this trial, have been recruited patients "in bad health condition" and as a bias it may have "distorted" the final result. For greater effectiveness it is necessary to find the "suitable" moment in which to administer such product.

For further information:
https://www.fiercepharma.com/pharma-asia/does-abbvie-s-hiv-drug-kaletra-also-works-covid-19-maybe-not-nejm-study-finds
The news / comments given in an online magazine specialized in the pharmaceutical industry.

https://www.nejm.org/doi/full/10.1056/NEJMoa2001282
Here the full scientific article.

.....
https://www.npr.org/sections/health-shots/2020/03/21/819099156/might-the-experimental-drug-remdesivir-work-against-covid-19

There is an interesting article on EvaluatePharma regarding remdesvir and expense related clinical development
https://www.evaluate.com/vantage/articles/news/corporate-strategy/estimating-cost-covid-19-antiviral-development

Phase III trials of Gilead’s remdesivir are likely to be the most expensive ventures right now; the US biotech has indicated that initial data should emerge before the end of March. This readout represents the world’s nearest-term chance of finding a treatment for the sometimes deadly respiratory symptoms caused by this particular coronavirus.

According to EvaluatePharma Vision’s R&D Costs module, these trials will probably cost Gilead around $150m to run. Estimates of the phase III trials being run in China are also included – the much lower figures reflect the fact that it is substantially cheaper to run studies in this region. A description of how these costs are calculated is below.

Gilead can afford this, of course, and should remdesivir prove effective the commercial return is likely to be huge, notwithstanding the company claiming their efforts are not rooted in the commercial. Roche has booked cumulative sales of $15.9bn of Tamiflu since it was launched in 1999; annual sales peaked at just over $1bn in 2014. These figures exclude sales booked by the other companies that make it

[bitbollo]

Please find HERE a very interesting resource regarding "Genomic epidemiology of novel coronavirus" ¹ with lot of data!

Yesterday² (March 22th 2020) I made this video You can play by clicking here.

[¹ Nextstrain.org aims to provide a real-time snapshot of evolving pathogen populations and to provide interactive data visualizations to virologists, epidemiologists, public health officials, and community scientists. Through interactive data visualizations, we aim to allow exploration of continually up-to-date datasets, providing a novel surveillance tool to the scientific and public health communities.

[² This video has been originally posted in Italian forum section ]

[o_e_l_e_o]

Once more, as stated in the OP, this thread is for evidence based discussion about treatment strategies specific to SARS-CoV-2. Much like discussion surrounding the influenza vaccine on the previous page, discussion about vitamin C megadosing for the common cold is entirely off topic. There are plenty of other threads where such discussion would be more suitable.

[CoinCube]

Once more, as stated in the OP, this thread is for evidence based discussion about treatment strategies specific to SARS-CoV-2. Much like discussion surrounding the influenza vaccine on the previous page, discussion about vitamin C megadosing for the common cold is entirely off topic. There are plenty of other threads where such discussion would be more suitable.

Your thread your rules. I have reposted the information on potential immune boosting supplements here:

https://bitcointalk.org/index.php?topic=5220206.msg54083990#msg54083990

I do disagree that this is off topic. We are just at the start of this and already there is a nationwide shortages of protective gear.

Coronavirus: Pleas go out for healthcare workers facing shortages of protective gear
https://www.msn.com/en-us/news/us/coronavirus-pleas-go-out-for-healthcare-workers-facing-shortages-of-protective-gear/ar-BB11B5Uk

Many front line healthcare workers are very likely to be placed in situations where they must treat patients with insufficient protective equipment. Any comprehensive treatment strategy for SARS-CoV-2 at this point must in addition to the typical treatment algorithms also include the following.

1) Developing a plan for treatment when new supplies of typically disposable protective equipment cannot be obtained.
2) Assessing personnel risk and determining which personnel should or should not be allowed to enter situations that carry high risk for exposure.
3) Risk mitigation for the inevitable high numbers of healthcare worker who will contract this on the job.

I would make the case that immune boosting supplements fall into #3 and are therefore relevant to a discussion of treatment strategies for SARS-CoV-2. However, I realize that that this not the direction you want this thread to go in so I will refrain posting any further discussion of supplements in this thread.

[bitbollo]

Latest updates from FiercePharma and Evaluate about new treatments for COVID-19 infection.
Please find below a short summary and various references.
I will keep posting information about new treatments only on this post (LAST and FINAL EDIT/UPDATE March 27th at 09:34)

I cannot share other informations and I can't update this post anymore because even my company will work in a clinical trial related COVID19 (public announcement not done)
Thanks to all and STAY SAFE!

KALETRA® (ALUVIA®) - Lopinavir/Ritonavir - Abbvie
AbbVie will not enforce global patent rights on all formulations of HIV med Kaletra (Aluvia) as the drug is being evaluated to treat severe COVID-19 in several clinical trials.
The move would free countries to purchase Kaletra generics in the event of a shortage or if the drug is found to be effective in treating COVID-19 patients. ¹

Remdesivir - Gilead
Gilead Sciences temporarily stopped granting patients emergency access to remdesivir under compassionate use due to an “exponential increase” in requests over the last few days, the company said Sunday. Exceptions will be made for pregnant women and children under 18 with severe COVID-19, the disease caused by the novel coronavirus.²

ACTMERA® - Tocilizumab - Genetech (Roche subsidiary)
FDA has approved a randomized, double-blind, placebo-controlled Phase III clinical trial in collaboration with the Biomedical Advanced Research and Development Authority (BARDA) to evaluate the safety and efficacy of intravenous Actemra® (tocilizumab) plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia.³

INOpulse®  - Nitric oxide (iNO) delivery system - Bellerophon
FDA Grants Bellerophon Emergency Expanded Access for INOpulse® for the Treatment of COVID-19 Virus. ⁴

Blood Plasma-Derived Antibodies - Takeda
Takeda Pharmaceutical Co. said its blood plasma-derived therapy against coronavirus currently in development has the potential to be among the first approved treatments for the deadly pathogen.⁵

Chloroquine Phosphate Hydroxychloroquine Sulphate - Ipca Laboratories
The FDA has lifted an import alert on India's Ipca Laboratories, one of makers of chloroquine (Active Product Ingredient) of this anti-malaria drug that could hold promise in managing and treating COVID-19 ⁶

Avigan® Favilavir® - Favipiravir - Fujifilm's
Chinese Clinical trial data demonstrated reduced viral load and improved X-Rays in treated patients.
However Japanese Officials note that it need to be used early, since the drug not appear to be as effective in people with severe symptoms. According to the same reference, it could be approved as early as May ⁷

Sylvant® - Siltuximab - Eusa Pharma
They are running an observational study on compassionate use in patients with serious complications of COVID-19 and the opportunity to generate data to understand the potential for IL-6 blockade in these patients. ⁸

Nafamostat Mesylate [generic drug] - Futhan® -  Nichi-iko Pharmaceutical Co. (producer)
A blood thinner used to treat pancreatitis and kidney disease has been identified as a potential therapy for COVID-19 patients. Clinical trials in Japan possibly set to begin in March 2020 ⁹

PUL-042 - Pulmotect  [new treatment added on this list March 24th 03:53 PM]
This is a prevention study that has lead positive data in preclinical stage. Phase I has been completed. Phase II to be initiated this year according the statement on reference¹⁰

SNG001 - Synairgen [new treatment added on this list March 25th 20:40 PM]
This company will start a Phase II trial (double blind and placebo controlled) in COVID-19 patients according to their statement "imminently"
¹¹

INOmax® - Nitric oxide (iNO) Mallinckrodt [new treatment added on this list March 25th 20:40PM]
They will start to evaluate the evidence of efficacy about their iNO delivery system for pulmonary complications associated with coronavirus.
(first announcement made on March 12th 2020)
¹²

remestemcel-L - Mesoblast [new treatment added on this list March 25th 20:40 PM]
Plans to evaluate its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L in patients with acute respiratory distress syndrome (ARDS) caused by coronavirus (COVID-19) ¹³
(first announcement made on March 10th 2020)

(LAST and FINAL EDIT/UPDATE March 27th at 09:33)
I cannot share other informations and I can't update this post anymore because even my company will work in a clinical trial related COVID19 (public announcement not done)
Thanks to all and STAY SAFE!

[There is actually no treatment approved for COVID-19. I am not involved in any of these companies.
Visit FiercePharma or visit Evaluatefor further information and updates on COVID-19.]
[Legend= Brand Name® - API (Active Pharmaceutical Ingredient) - Company Name]

¹ https://www.ft.com/content/5a7a9658-6d1f-11ea-89df-41bea055720b
² https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-access-to-remdesivir-outside-of-clinical-trials
³ https://www.businesswire.com/news/home/20200323005166/en/Genentech-Announces-FDA-Approval-Clinical-Trial-Actemra
⁴http://investors.bellerophon.com/news-releases/news-release-details/fda-grants-bellerophon-emergency-expanded-access-inopulser
⁵ https://www.bnnbloomberg.ca/drugmaker-takeda-sees-speedy-approval-of-coronavirus-treatment-1.1407334
⁶ https://www.bseindia.com/xml-data/corpfiling/AttachLive/af31e003-575e-4550-b6f2-c1340aec82e9.pdf
⁷ https://pbs.twimg.com/media/ETadjJVWoAAXv-4?format=jpg&name=4096x4096
⁸ https://www.biospace.com/article/releases/eusa-pharma-and-the-papa-giovanni-xxiii-hospital-bergamo-italy-announce-initiation-of-an-observational-case-control-study-of-siltuximab-in-patients-with-covid-19-who-have-developed-serious-respiratory-complications/
⁹ https://www.bnnbloomberg.ca/japanese-researchers-to-test-blood-thinner-for-virus-treatment-1.1407980
¹⁰ https://pulmotect.com/wp-content/uploads/2020/01/20201_Coronavirus_PR_Final.pdf
¹¹ https://www.synairgen.com/wp-content/uploads/2020/03/200318-Synairgen-to-start-trial-of-SNG001-in-COVID-19-imminently-.pdf
¹² https://mallinckrodt.gcs-web.com/node/26576/pdf
¹³ http://investorsmedia.mesoblast.com/static-files/c1428818-0b9f-44f9-bb4f-79ad518002cc

[bitbollo]

Latest clinical trials results posted today March 24th 2020, please find below a short summary with references.

According to this small study, as reported on Fiercepharma hydroxychloroquine has provided disappointing results vs conventional treatment.

...Hydroxychloroquine, a more tolerable form of chloroquine, didn’t top placebo at clearing the coronavirus among mild Chinese patients, or helping them reach normal temperature sooner.
.... used on top of conventional treatments, cleared the virus in 13 (86.7%) cases on day 7, while 14 (93.3%) patients in the control group the virus cleared, according to a study abstract Raffat obtained. One patient on the malaria med progressed to severe during the treatment.
.... The only positive signal was disease progression shown on CT scans, which five hydroxychloroquine cases showed, versus seven in the control group. .... (however) the trial size was simply too small to draw conclusions.

As claimed by the same news on Fiercepharma there is also another trial fail published today in this preprint paper , where subjects have been randomized to lopinavir/ritonavir (Kaletra® also known as Aluvia®) or Umifenovir (Arbidol®) or no antiviral medication as control (2:2:1)

... exploring the efficacy and safety of lopinavir/ritonavir (LPV/r) or arbidol monotherapy treating mild/moderate COVID-19 patients.
... The positive-to-negative conversion rates of SARS-CoV-2 nucleic acid at day 7 and 14 did not show significant differences in the LPV/r group (42.9%, 76.2%), the arbidol group (62.5%, 87.5%) and the control group (71.4%, 71.4%) (all P>0.53). No statistical differences were found among three groups in the rates of antipyresis, cough alleviation, improvement of chest CT or the deterioration rate of clinical status (all P > 0.05).
Overall, 5 (23.8%) patients in the LPV/r group experienced adverse events during the follow-up period. No apparent adverse events occurred in the arbidol or control group.
.... (however) Due to the limitation of small sample size, further verification is needed in the future.

(LAST and FINAL EDIT/UPDATE March 27th at 09:34)

I cannot share other informations and I can't update this post anymore because even my company will work in a clinical trial related COVID19 (public announcement not done)
Thanks to all and STAY SAFE!

[bitbollo]

An interesting list of vaccine projects has been posted on Evaluate Pharma, please find below these updates:

Johnson & Johnson Collaboration with Beth Israel Deaconess Medical Center
Heat Biologics Collaboration with University of Miami
Anges Collaboration with Osaka University
Epivax Collaboration with University of Georgia
Generex Collaboration with Epivax
Arcturus Collaboration with Duke-NUS Medical School
Inovio

[erre]

IMPORTANT NOTICE: the above time values are MEDIANS, not the upper limited of a confidence interval.

Considering that an asymptomatic is no more contagious after 2 weeks because that's the median value is very imprudent (50% will be still contagious if the distribution is gaussian).

This common error is killing people in italy.

[fillippone]

IMPORTANT NOTICE: the above time values are MEDIANS, not the upper limited of a confidence interval.

Considering that an asymptomatic is no more contagious after 2 weeks because that's the median value is very imprudent (50% will be still contagious if the distribution is gaussian).

This common error is killing people in italy.

Very interesting @erre.
Could you please clarify what "immune" means?
I heard, I might be wrong here, that second infections were observed in recovered patients. "Immune" makes me think that second infections aren't even possible.

[erre]

IMPORTANT NOTICE: the above time values are MEDIANS, not the upper limited of a confidence interval.

Considering that an asymptomatic is no more contagious after 2 weeks because that's the median value is very imprudent (50% will be still contagious if the distribution is gaussian).

This common error is killing people in italy.

Very interesting @erre.
Could you please clarify what "immune" means?
I heard, I might be wrong here, that second infections were observed in recovered patients. "Immune" makes me think that second infections aren't even possible.

You are immune when you produce specific antibodies for the disease.
Not every disease grant immunity forever, but it's reasonable that the few observed remission cases are an exception.

[PrimeNumber7]

I am not sure what type of practice you have, however if you were treating a patient with COVID-19, can you explain the reasons why you would prescribe someone Hydroxychloroquine to treat the disease? and also can you explain some of the reasons why you would not prescribe Hydroxychloroquine?

This drug has not been proven in effectiveness in treating COVID-19, however clinical trials required to show proof can take time that hundreds of thousands of people may not have, and there is some anecdotal evidence that it works. 

[franky1]

I am not sure what type of practice you have, however if you were treating a patient with COVID-19, can you explain the reasons why you would prescribe someone Hydroxychloroquine to treat the disease? and also can you explain some of the reasons why you would not prescribe Hydroxychloroquine?

This drug has not been proven in effectiveness in treating COVID-19, however clinical trials required to show proof can take time that hundreds of thousands of people may not have, and there is some anecdotal evidence that it works. 

studies show its effectiveness as a antiviral is not much/any. hense also needing an antiviral as part of treatment. but it has shown some effectiveness at dampening the immuni inflamatory response that causes the breathing distress.

there is not single magic pill and even if able to breathe easier doesnt mean your cured of the actual viral invasion. your just symptomless.
taking these drugs as immuno suppressers when not having an immuno reaction can actually harm you and when you get corona you may end up being worse than you would of if you didnt take it prior to getting corona.

thats why there is stil questions around if its a good enough drug for a certain job and when is best to administer it. as administering it even during ARDS (respiratory distress) can exacerbate the other symptoms

[estenity]

studies show its effectiveness as a antiviral is not much/any. hense also needing an antiviral as part of treatment. but it has shown some effectiveness at dampening the immuni inflamatory response that causes the breathing distress.

there is not single magic pill and even if able to breathe easier doesnt mean your cured of the actual viral invasion. your just symptomless.
taking these drugs as immuno suppressers when not having an immuno reaction can actually harm you and when you get corona you may end up being worse than you would of if you didnt take it prior to getting corona.

thats why there is stil questions around if its a good enough drug for a certain job and when is best to administer it. as administering it even during ARDS (respiratory distress) can exacerbate the other symptoms

thank you for explaining, but a  proportion of patients die from "cytokine storm ", sometimes brutally in the street.
so you have to precise the indications.

[JayJuanGee]

studies show its effectiveness as a antiviral is not much/any. hense also needing an antiviral as part of treatment. but it has shown some effectiveness at dampening the immuni inflamatory response that causes the breathing distress.

there is not single magic pill and even if able to breathe easier doesnt mean your cured of the actual viral invasion. your just symptomless.
taking these drugs as immuno suppressers when not having an immuno reaction can actually harm you and when you get corona you may end up being worse than you would of if you didnt take it prior to getting corona.

thats why there is stil questions around if its a good enough drug for a certain job and when is best to administer it. as administering it even during ARDS (respiratory distress) can exacerbate the other symptoms

thank you for explaining, but a  proportion of patients die from "cytokine storm ", sometimes brutally in the street.
so you have to precise the indications.

I was not sure what cytokine storm was, so I did a quick google search, and I found this short article.

https://www.newscientist.com/term/cytokine-storm/

Of course, there were plenty of other articles, but this one at least gave a quick overview of the concept.

[tvbcof]

thank you for explaining, but a  proportion of patients die from "cytokine storm ", sometimes brutally in the street.
so you have to precise the indications.

I was not sure what cytokine storm was, so I did a quick google search, and I found this short article.

https://www.newscientist.com/term/cytokine-storm/

Of course, there were plenty of other articles, but this one at least gave a quick overview of the concept.

That's what the animal test subjects dropped from in startling numbers before they gave up on the last coronavirus vaccine was attempted 10 years ago.  Just FWIW.  But since this post posses some questions about vaccines it will be deleted on this 'self-moderated' thread.

[bitbollo]

About hydroxychloroquine (HCQ) there is a big HYPE...
Ruling out France, where there is a medical doctor that made the first paper (find below a short analysis) https://bitcointalk.org/index.php?topic=5232377.msg54066125#msg54066125
and announcement in twitter
https://twitter.com/AceClearance/status/1244243333322506240
with AWESOME RESULTS (no twitter is not a peer reviewed scientific journal and peers evaluate papers not conclusions   ) rest of Europe, with EMA authority (European Medicine Agency) has taken a clear position:

European Medicines Agency restricted general use of the drugs—already approved to treat malaria and autoimmune diseases—to patients taking them for approved indications. COVID-19 patients can receive the drugs as part of clinical trials or through national emergency use programs, the EMA said.

https://www.ema.europa.eu/en/news/covid-19-chloroquine-hydroxychloroquine-only-be-used-clinical-trials-emergency-use-programmes

Fun Fact,
as I have highlighted to some USA member   ... most of people continue to speak about HQC thanks to a "presidential support".

"Unlike FDA, European regulators refuse to clear chloroquine for COVID-19 without data"
Chloroquine and hydroxychloroquine have drawn more attention— and certainly more presidential support —than any other drug during the global quest to find an effective coronavirus therapy.

https://www.fiercepharma.com/pharma/europe-locks-down-chloroquine-scripts-as-researchers-china-report-positive-controlled-covid

"The suspect science behind Trump’s chloroquine claims"
Trump’s trumpeting of chloroquine may have encouraged at least one fatal outcome. As we reported, a Phoenix couple who heard Trump’s briefing took doses of a chloroquine preparation they had at hand to treat their fish tank; the husband died and his wife landed in critical condition before recovering.

https://www.latimes.com/business/story/2020-04-01/trump-chloroquine-coronavirus-bad-science-hiltzik-column

[o_e_l_e_o]

-snip-

Where I am working, almost all patients are being randomized in to a trial. One arm of said trials includes hydroxychloroquine therapy. So there isn't really a medical decision to be made regarding treatment - if they are in the treatment arm they receive it, if they are in any of the other arms, they don't.

Yes, there are anecdotal reports, but there also anecdotal reports of it making no difference, and it carries a number of not-insignificant side effects, including affecting cardiac repolarization and glycemic control.

[franky1]

-snip-

Where I am working, almost all patients are being randomized in to a trial. One arm of said trials includes hydroxychloroquine therapy. So there isn't really a medical decision to be made regarding treatment - if they are in the treatment arm they receive it, if they are in any of the other arms, they don't.

Yes, there are anecdotal reports, but there also anecdotal reports of it making no difference, and it carries a number of not-insignificant side effects, including affecting cardiac repolarization and glycemic control.

are they including patients in the 'atrisk' group like pregnant, heart issues, diabetic.

i only ask because i have relatives with heart/diabetic issues and if(small if) they did get severe symptoms of respiratory distress from corona and need treatment where these 'trials' are used more fluidly. would doctors be sensible to decline them out of these 'trials' and give other treatments instead. or is it just random selection