This post was written by several members of the RxISK Team drawing on the work of Jorge Carrasco – see below. There is a prior RxISK post on DRESS Syndrome – No Way to Treat a Lady.
María Elisa Rangel was 38 and a mother of four children when she signed up for a phase 1 clinical trial in April 2015. They needed the money.
The drug was cenobamate, marketed by SK Life Science which is a subsidiary of SK Biopharmaceuticals, the second largest South Korean conglomerate.
The trial was run by Celerion, a CRO (Contract Research Organization) in Kempe, Arizona, USA.
Thirty-two days into the trial she developed severe side effects and was later admitted to hospital. She collapsed and died 50 days later.
The autopsy showed eosinophilic myocarditis due to DRESS – Drug Reaction with Eosinophilia and Systemic Symptoms. Cenobamate had previously been linked to DRESS. which has 10% mortality
Rangel’s family were presented with hospital bills for over $26,000. In March 2022 SK Life Science and Celerion agreed an out-of-court settlement with her family for an undisclosed sum.
The story starts about 2005 when cenobamate, otherwise known as YKP3089, was developed by South Korean company SK Biopharmaceuticals, hoping to develop it as an anti-anxiety drug. It was later claimed to be effective in the treatment of epilepsy, and is now on the market for this.
The only Phase 1 (healthy volunteer) randomised controlled trial, YKP3089C020, was run by Celerion in Kempe, Arizona on behalf of SK Biopharmaceuticals.
“The name Celerion is derived from the Latin celeritas meaning swiftness and speed. Our name reflects our founding principle – to help our clients get their products to the market faster.”
Celerion now has facilities across North America, Europe, and Asia, in 30 countries worldwide, employs more than 1,000 full-time scientific and medical personnel … while upholding the highest standard of ethics. Their facilities offer over 600 beds and are among the most extensive in the industry.
The Chief Principal Investigator (PI) for Celerion was Dennis Swearingen MD, also from Kempe. The research data were analysed by Clario (Philadelphia, Pennsylvania), on behalf of SK Biopharmaceuticals but strangely the results were not submitted for publication until July 2021.
In 2015 – the year of the fatal trial Swearingen earned $915,404.62 associated research payments from Merck Sharp & Dohme LLC and $1,222,158.55 research payments from Quebec-based Valeant Pharmaceuticals International, in addition to his earnings as an employee of Celerion.
(In 2015, in one of the biggest pharmaceutical company scandals, the value of Valeant, which had a reputation for buying up smaller companies and then raising the prices of their products, plummeted when it was revealed that they were illegally running a pharmacy company, Philidor Rx which fraudulently dispensed their products. The remnants of Valeant were rebranded as Bausch Health.)
Principal Investigators: are people who work with private labs, where they do trials. They have no great medical expertise – their expertise is in not getting in the way of running trials not in diagnosing and treating adverse reactions.
Another player is William Elliot Rosenfeld MD. Seventy year-old Rosenfield of Saint Louis, Missouri, is a neurologist. In 2021 he pocketed $622,351.89, mainly in consulting fees, from SK Life Science – makers of cenobamate, making him their highest paid consultant. Over the last three years he has co-authored thirteen ghost-written articles about cenobamate published in six different journals.
Rikki has been a volunteer for Celerion 99 times. Its worth listening to him Say Hi to Rikki.
The trial enrolled 108 subjects for a 65 day study in early 2015 as part of its development as an anticonvulsant.
This was a so-called “Thorough QT study” to assess the effects of therapeutic and supratherapeutic cenobamate doses on the heart rhythm in healthy adult subjects. This was the trial in which Maria Rangel died.
Rangel, a healthy undocumented immigrant from Mexico, had no health insurance. She volunteered in April 2015 and became subject no 95 in the trial. She was one of 54 subjects randomised to treatment arm A.
After taking increasing dosages of cenobamate for 32 days she became unwell. Her illness started with an itchy rash on her face which became widespread. Her clinical course and blood test results are documented María Rangel’s liver enzyme results (page 369 onwards).
She reattended Celerion’s clinic the next day. The rash was more extensive. She was given antihistamine cream and tablets. Her blood tests were abnormal: one of her liver function tests was six times higher than that recorded before she started cenobamate. Her trial medication was stopped.
No action was taken over the abnormal results. She reattended six days later, breathless and with a fever. She was referred to a local emergency department, where a “drug rash” was diagnosed. She was sent home on oral steroids. Over the next five days she attended Celerion’s clinic three times – each time her blood tests showing serious worsening of her liver function.
She experienced several mild to moderate adverse events in the days and weeks after being discontinued from the study, including depressed mood, face swelling, anxiety, back pain, alopecia, ecchymosis, blurred vision, chest pain, dyspnea, palpitations, headache, cough, fatigue, and asthenia. Her depressed mood began 7 days after the last dose of study drug and Dr Swearingen considered it but not the other problems possibly related to study drug.
The remaining events began 25 to 50 days after the last dose and [he] considered them all unlikely or unrelated to study drug.
Two days after a skin biopsy had confirmed DRESS she was finally admitted to hospital for treatment on day 44.
Thereafter she frequently attended the trial centre and hospitals, running up bills for her family totalling over $26,000.
The day before she died, 86 days after she entered the trial, she developed chest pains. She phoned Celerion and was reminded to go the emergency room for chest pain. The clinic staff also suggested relaxation techniques, such as taking a warm bath or listening to music.
The next day she was found collapsed by her husband and she was unable to be resuscitated. Post-mortem examination showed she died from a heart attack caused by “eosinophilic myocarditis due to DRESS, with findings of pleural effusions, pericardial effusion, pulmonary oedema, cardiomyopathy, and necrotizing myocarditis”.
She is one of three people who have been documented as developing DRESS whilst taking cenobamate. A 36-year-old white female with epilepsy entered the same study YKP3089C017 early in 2014. She developed DRESS 24 days into the trial and was admitted as an emergency with a rash and fever. She improved on treatment with steroids, but was lost to follow-up.
SK Biopharmaceuticals would have been aware of this serious event but Rangel was not warned of the probable association.
María’s widowed husband, Cristobal Legarda sued Celerion, SK Life Science and Swearingen in 2016
DRESS is often disingenuously referred to as a “skin condition” in drug trial adverse events tables.
Seven years ago RxISK carried the harrowing story of a 16 year-old girl’s death from DRESS caused by an antibiotic. Allopurinol and virtually all anticonvulsants are known to cause this condition, as are some vaccines including for Covid.
A review article of 172 patients with DRESS published in the American Journal of Medicine in 2011 had shown that epilepsy drugs were one of the commoner causes. Despite this many doctors are not aware of DRESS.
The DRESS Syndrome Foundation list the following common Early DRESS Symptoms:
If you have read this far, you will know more about DRESS than most doctors.
If you are taking medication and develop any of the above symptoms:
DRESS syndrome is evolving. There are an increasing number of conditions linked to meds including Eosinophilic Oesophagitis and Eosinophilic Stomatitis. The DRESS sydrome foundation recognise variants that don’t show Eosinophilia. Oesophagitis and Stomatitis affect surfaces of the body – they are not inside the body – and can be thought of as rashes of the mucosal membranes.
Having your oesophagus or mouth affected is less of a problem than having your heart affected and so these conditions are even less recognized but are happening ever more often with the increasing use of anticonvulsants, like lamotrigine, and some antibiotics.
If you have something odd that doctors aren’t recognizing which doesn’t fit the classic DRESS picture – think atypical DRESS and raise it with your doctor.
Cenobamate is now marketed as Xcopri (US) and Ontozry (EU). In the last three years it has been licenced for the treatment of patients with focal onset seizures, mainly as an add-on treatment for patients whose epilepsy is not controlled by other medication.
Meprobamate, which is related to cenobamate, is one of the most famous drugs in the history of medicine. In the 1950s, marketed as Miltown, it was the first tranquilizer and helped usher in the psychopharm era. It was also recognized to have anti-seizure activity.
Felbamate is another closely related drug which has been marketed for anti-seizure effects from the 1980s onwards but is rarely used now.
All the bamates and related drugs like retigabine and flupirtine are weakly anti-seizure and come with risks of suicide and DRESS and related syndromes. Nobody talks about these problems with meprobamate – there is silence about its eclipse. It was the best-selling psychotropic drug in the mid to late 1950s but by the early 1960s it had vanished – replaced by Librium and Valium.
The other angle on the Cenobamate story is that for three decades companies have bought drugs like lamotrigine, pregabalin and gabapentin on the market as anti-convulsants but with a view to encourage their leakage into the treatment of anxiety, or anxiety rebranded as bipolar disorder – which is where the money is.
This rebranding helps get regulatory approval for another reason. A straight-up anxiolytic that caused problems like DRESS syndrome would never be approved but lamotrigine gets approval for the treatment of a serious disorder like epilepsy because much more risks can be tolerated for epilepsy than for anxiety. The marketing then leads to a leakage into other much more lucrative areas. Shipwreck of the Singular has a lot more on this strategy.
The “Thorough QT study” was performed as a requirement of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Guidance 14 states:
“If not precluded by considerations of safety or tolerability due to adverse effects, the drug should be tested at substantial multiples of the anticipated maximum therapeutic exposure.”
The plan was for Rangel to take up to 500mg daily of cenobamate, whereas the normal therapeutic dose is 200mg.
Is it justifiable that any drug should be tested in volunteers “at substantial multiples of the anticipated maximum therapeutic exposure”?
Was Celerion’s founding principle: “to help our clients get their products to the market faster” part of the problem as the cenobamate dosage was increased over a rather short timescale, saving money. In later clinical practice, doctors have been told to increase the dose slowly – as they are told with lamotrigine.
Poverty impacts on many clinical trial volunteers in two ways. Many volunteers can’t afford medical insurance – which may not cover participating in trials. This likely inhibits the investigating clinicians from referring them for specialist care when it is needed.
If they are admitted to hospital volunteers will struggle to pay their bills. It is well recognised that trial sponsors will not cover illness arising during a trial unless the trial drug can be proved to be responsible.
There are a few clues in the FDA narrative (p376+) suggesting that María Rangel had financial problems.
“She again reported feeling sad due to being homebound, and concern over finances”
“She stated that she had increased stressors in her home life and finances over the past few days”
“She also reported ongoing stress with regard to family finances and the need to find childcare for her return visits.”
Despite being “undocumented”, see Celerion’s website March 2015, she was allowed to participate in the trial.
The family were unable to afford a headstone at Greenwood Memory Lawn Cemetery in Phoenix, Arizona, where she was buried on August 19 2015.
Jorge Carrasco is an award-winning Digital Journalist at NBC Universal Telemundo Enterprises in Miami Beach. In 2017, he won the Gabriel García Márquez Award for Journalism in the Text category. He was a Health Journalism Fellow at University of South California: see for instance “Latinos in need turn to paid clinical trials as full-time jobs”. As an investigative journalist he has exposed some of the issues associated with clinical trials in Florida. He published the story of María Rangel in Spanish.
On March 1, 2022, the family lawyer Daniel Treon confirmed that Celerion and SK Life Science, Inc. had reached an out-of-court settlement with Maria’s husband Cristobal Legarda, citing terms of confidentiality. This settlement happened a few weeks before going to trial.
Celerion said in an emailed statement that the case had been “settled by mutual agreement of the parties” and that its mission is “to help our customers get their medicines to market quickly and safely so that they have an effect on lives of our families, friends and people in need around the world.”
Citing the settlement with the Legarda-Rangel family, SK Life Science Inc. declined to answer questions about the case, but a company spokesman explained in an email that the drugmaker’s “top priority” is “the safety of patients and participants in our clinical trials”.
Before reaching the settlement, Celerion, SK Life Science Inc. and the study’s investigators declined multiple interview requests during the Noticias Telemundo investigation, claiming that the six-year litigation prevented them from commenting on the case.
New Drug Filing for Cenobamate Accepted for Review in Canada and Israel
NEWS PROVIDED BY
Aug 09, 2022, 09:00 ET
PANGYO, South Korea, Aug. 9, 2022 /PRNewswire/ — SK Biopharmaceuticals, Co., Ltd. announced that Health Canada has accepted Paladin Labs Inc.’s filing of a New Drug Submission (NDS) for cenobamate as an adjunctive therapy for the management of partial-onset seizures in adults with epilepsy who are not satisfactorily controlled with conventional therapy. If Health Canada approves this NDS, Paladin Labs would be able to launch cenobamate in Canada.
Cenobamate is a tetrazole carbamate anticonvulsant used as therapy of partial onset seizures in adults. Cenobamate is associated with a low-to-moderate rate of serum aminotransferase elevations during therapy and has been linked to cases of clinically apparent liver injury usually in the context of a multiorgan hypersensitivity syndrome such as drug reaction with eosinophilia and systemic symptoms (DRESS).
At the time of the study data cutoff, 1,037 participants were exposed to cenobamate for at least 196 days. There were 4 sudden deaths, 3 of which were reported as occurring because of traumatic intracranial hemorrhage (ICH), motor vehicle accident, and respiratory failure; there was no autopsy in the 4th death.
No subsequent cases of DRESS were reported.9
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“An Alarm that must be heard.” …
Gas Lighting on Trial(s)
Maria was to my mind definitely a woman subjected to gaslighting – not yet, ,perhaps never a criminal offence although contributing to deaths.
‘Sixty seconds on . . . medical gaslighting’ (most of us , men as well,could contribute a lot more than 60 secs.)
http://dx.doi.org/10.1136/bmj.o1974 Published: 09 August 2022
Is this something to do with the Ingrid Bergman movie?
That would be the 1944 film Gaslight, which tells the story of a man who manipulates his wife to such an
extent that she doubts her own sanity. Since then, the term gaslighting has been widely used to describe any
form of emotional abuse that makes someone question their own grasp of reality.
Is Medical Gaslighting the sequel?
No, it’s a term usually used to describe when a medical professional wrongly blames a patient’s symptoms
on psychological factors such as stress or anxiety or tells them they are not really sick.
Never heard of it—I think you’re imagining it
Patients are increasingly sharing their stories of medical gaslighting on social media sites such as Instagram
#medicalgaslighting. And two articles on the subject published in the New York Times this
year have prompted thousands of responses.1 2 In one article a woman described going to a cardiologist with
chest pains and being told to simply exercise more. Another woman who described weight loss, losing her
hair, and developing a full body rash in her 20s was told by her male doctor that she was “young, healthy, 2
and just lazy.” She was later given a diagnosis of the autoimmune disorder Graves’ disease.
Are women particularly at risk?
Women have reported that health problems such as endometriosis, fibromyalgia, and irritable bowel syndrome
are often downplayed or dismissed by doctors. And studies have shown that, when compared with men
women face longer waits to be given a diagnosis of cancer or heart disease, for example.3 But black people,
geriatric patients, and LGBT+ people are also more likely to have their symptoms dismissed without a full
Is it mainly doctors dismissing patients’ concerns?
Not just that. A female Canadian doctor described being gaslit several times by colleagues in professional
settings. She described specialist colleagues using their status to try to convince her of something she knew.
to be false or not in the best interests of her patients.
Is medical gaslighting becoming more common?
The term has been used widely in connection with long covid, particularly early on in the pandemic. Some
patients who were still experiencing symptoms months after infection with SARS-CoV-2 thought that they
were not treated seriously, or investigated fully, by doctors.5 6
1 Women are calling out “medical gaslighting.” New York Times. Mar 2022. https://www.nytimes.com/2022/03/28/well/live/gaslighting-doctors-patients
2 Feeling dismissed? How to spot“medical gaslighting” and what to do about it. New York Times. July 2022. https://www.nytimes.com/2022/07/29/well/mind/med
Wu J, Gale CP, Hall M, etal. Editor’s Choice – Impact of initial hospital diagnosis on mortality for acute myocardial infarction: A national cohort study. Eur Heart
J Acute Cardiovasc Care 2018;7:-48. doi: 10.1177/2048872616661693. pmid: 27574333
4 Fraser S. The toxic power dynamics of gaslighting in medicine. Can Fam Physician 2021;67:-8. doi: 10.46747/cfp.6705367. pmid: 33980633
Mariani M. The great gaslighting: how covid longhaulers are still fighting for recognition. Guardian. Feb 2022. https://www.theguardian.com/soci m
the bmj | BMJ 2022;378:o1974 | doi: 10.1136/bmj.o1974 1
AdDRESSing a different type of Dress – Seroxat Secrets was Here…
Secret of the Tomb…
GSK pouring salt into your wounds…
August 3, 2022 — admin
So… it’s been a while and as I’m sure people will be aware of, I don’t keep this blog up to date anymore.
There has been lots of water under the bridge and I’ve been lucky in that I have (almost completely) recovered and there are so many more campaigners out in the world today than when I started writing this back in 2006.
Sometimes though I hear some news that makes me want to scream – and today is one of those days.
I saw this in a tweet – GSK Discontinues Production of Liquid Paroxetine (Seroxat).
The tweet was from the good folks at Mad in America and I really had to read it a few times to let the news sink in… it’s beyond belief GSK is going to stop making liquid Seroxat.
For all too many patients, the liquid formulation is the ONLY way that they can slowly taper off the drug in a way that works. With no tapering strips available (I don’t think?) or small dose tablets (1mg/0.5mg), people are going to be fucked without the liquid.
I know – it took me almost 24 months to slowly reduce using the liquid back in 2004. Even using the liquid it was almost unbearable – and unachievable.
And GSK have the absolute fucking brass neck to say“GSK has decided to discontinue manufacturing, supply and marketing of paroxetine hydrochloride oral suspension products. We recognise that paroxetine hydrochloride oral suspension is an important medicine for some patients and regret any inconvenience the discontinuation may cause.”
It’s clear that the current GSK is exactly the same as the old GlaxoSmithKline.
GSK does not care anything for patients that have been – and continue to be – damaged by their drug.
I have no words.
August 3, 2017 — admin
Seroxat Secrets was a mine of information for those struggling with horrendous withdrawal and pumped up with chemicals from GlaxoSmithKline, and receiving this email just shows the passion people have retained for one of the most truly horrendous drugs ever to enter the market…
This blog is still live, a mighty Tome, much and so much work over the years. Loyalty goes a long way as with Truthman and Fid Blog
Who wants to invite Baum Hedlund to open an office in London…
Cut a deal with Fortitude Law and get their £9.33 million back…
And do something about Judge Lambert…
Ridiculous – (GSK has a case to answer)
The Fight for Pharma Accountability and Psychiatric Rights: Jim Gottstein, Esq
August 2, 2022
Awais Aftab, MD
For example, David Healy, MD, is on a mission to make the trial data available for review at the participant level, including being able to interview the participants. He makes the point it is outrageous the drug companies claim these data are trade secrets when volunteers risk harm for the benefit of society.
As David Healy has commented, “… everything we know about what pharma gets up to comes from legal actions in the US and a handful of lawyers like Gottstein.”2
new job is at the Natural History Museum
Government’s chief scientific adviser Sir Patrick Vallance will step down in April
Famed appearing in Covid briefings his new job is at the Natural History Museum
2013-06-14 — The RIAT team sends an email to GSK, Sir Andrew Witty (CEO) and Patrick Vallance (President of Pharmaceutical R&D), notifying them of the RIAT article publication and requesting that if they plan to restore any old GSK trials, they respond as soon as possible.
Sir Patrick Vallance, who taught me at medical school, has announced he’s stepping down as the Government’s chief scientific adviser. During the dark days of the pandemic, I felt safe knowing he was guiding our response. He’s served us all admirably and I hope he now enjoys a well-deserved rest. – Max Pemberton 9/822
Night at the Museum –
Night at the Museum: Secret of the Tomb…
Very glad to have the warning about DRESS Syndrome and meprobamate – because this drug is not “history” by any means. In the United States a drug called carisoprodol is commonly given as a “muscle relaxant” for pain and muscle spasms, especially with back injuries. Its brand name is SOMA (after the feel-good potion ladled out to the masses in Aldous Huxley’s Brave New World?). Meprobamate is its main metabolite. As the official leaflet makes clear, the first step in liver metabolism of this drug turns Soma into meprobamate:
Soma can definitely be habit-forming all by itself – and it’s also become a player in the US opioid crisis. A combination of hydrocodone, Xanax and Soma earned the nickname of “Holy Trinity” due to the intense high it produced. Prescriptions for that combo became a red flag for law enforcement that a pain clinic was operating as a “pill mill” supplying drugs to addicted patients and drug dealers.
Many (if by no means all) doctors know of Soma’s abuse potential – but I bet very few realize how dangerous an “allergic” or “hypersensitivity” reaction to this drug can be. Which means their patients will have no idea.
[…] 1) https://helpresearch.com/vef/load/b07724904e9bac82934dc6b70914c15c 2) https://www.synexusclinic.co.uk/refer-a-friend/ 3) https://clinicaltrials.gov/ct2/results?cntry=US&state=US%3AFL&recrs=a&ag… 4) https://www.nejm.org/doi/suppl/10.1056/NEJMoa2110345/suppl_file/nejmoa21… (table S3) 5) https://pdata0916.s3.us-east-2.amazonaws.com/pdocs/070122/125742_S1_M5_5… 6) https://rxisk.org/all-dressed-up-with-nowhere-to-go/ […]