A phase I clinical trial of the drug BIA 10-2474 conducted in France had a catastrophe, with 6 volunteers hospitalized after suffering adverse effects and 1 dying. The trial was testing the safety of escalating doses of the drug in 128 healthy volunteers. After volunteers received a higher dose on January 10, they began experiencing severe neurological symptoms like those of a stroke. The cause was unknown and investigations were launched while the trial was halted.

1. MAJOR PHASE I
CLINICAL TRIAL
CATASTROPHE IN
FRANCE
PRESENTED BY
GOPI PATEL
(FELLOW STUDENT AT AAPS)
PROFESSOR:- PEIVAND PIROUZI

2. • SPONSOR:- BIAL – PORTELA & Cª, S.A. PORTUGAL BASED PHARMA
COMPANY
• STUDY SITE:- BIOTRIAL CRO, RENNES, FRANCE
• PURPOSE:- To treat mood disorders, anxiety & movement
disorders related to neuro degenerative diseases associated with
Parkinson's disease, and chronic pain in people with cancer and
other conditions. .
• DRUG:- Referred to only by a codename, BIA 10-2474 The chemical
name of BIA-10-2474 is 3-(1-(cyclohexyl (methyl)carbamoyl)-1h-imidazol-4-
yl)pyridine 1-oxide (according to the clinical study protocol)

3. • OBJECTIVES:-
To assess the safety and tolerability of BIA-10-2474
after single & multiple oral doses and to investigate
the effect of food on the PK and PD of the drug.
• PHASE:- 1 STUDY
• PI:- DIDIER CHASSARD, MD
• DESIGN:- Double-blinded, randomised, placebo controlled,
combined single & multiple ascending dose
including food interaction study

4. • INCLUSION CRITERIA:-
• healthy male and female candidates between age 18-55
years.
• BMI between 19 and 30 kg/m2
• negative tests for hepatitis B hepatitis C, HIV-1, HIV-2
• negative screen for alcohol and drug abuse at screening
• non- smokers or ex-smokers(ceased smoking > 3 months)
• EXCLUSION CRITERIA:-
• Pregnant or breastfeeding women
• history of alcoholism or drug abuse
• history or presence of respiratory, gastrointestinal, renal
,hepatic, psychiatric, cardiovascular lymphatic diseases or
disorders.

5. • ANSM(NATIONAL AGENCY OF DRUG SAFETY) AUTHORIZED THE
TRIAL ON JUNE 26TH 2015
• START DATE:- JULY 09TH 2015 AT BIOTRIAL
• PREVIOUS TO PHASE-I TRIAL, DRUG BIA-10-2474 WAS TESTED ON
ANIMALS INCLUDING CHIMPANZEES.
• THE STUDY WILL BE PERFORMED IN FOUR PARTS: THE SINGLE
ASCENDING DOSE (SAD) PART, THE FOOD INTERACTION(FI) PART,
THE MULTIPLE ASCENDING DOSE(MAD) PART, AND A SPECIFIC PD
PART.
• THE TRIAL RECRUITED 128 HEALTHY VOLUNTEERS, WHO WERE
PAID €1,900 (US$2,060) EACH. 64 IN THE SAD, 12 IN FI, 32 IN
MAD, AND 20 IN PD PART.
• SUBJECT WILL PARTICIPATE IN STUDY FOR MAX. 13 WEEKS

6. STUDY PRODUCTS, DOSE AND MODE OF
ADMINISTRATION
NAME FORMULATION DOSES MODE OF
ADMINISTRATION
BIA 10-2474 Capsules, hard 0.25, 2.5 and 10mg Oral
Placebo Capsules, hard NA oral
• The study will be performed in four parts: the single ascending
dose (SAD) part, the food interaction(FI) part, the multiple
ascending dose(MAD) part, and a specific PD part.
• The participants were divided into 8 different groups.
• serious incidents in phase 1 studies are rare, but they can never
be completely excluded because a drug's behavior in animals
isn't always a good predictor of its effects in humans.

7. THE HOSPITAL IN RENNES, FRANCE, TO WHICH SIX PEOPLE
WERE TAKEN AFTER SUFFERING ADVERSE EFFECTS IN A
PHASE I CLINICAL TRIAL.
• The trial had tested escalating single doses of the drug without observing any
serious adverse side effects.
• 1st subject began taking higher dose of drug on Thursday Jan 07th 2016 and
symptoms appeared 3 days later.
• 1st participant to fall ill experienced adverse symptoms on 10 January and died
on January 17th 2016.
• Other 5 participants were given the repeat multiple dose of drug on 10th Jan
2016 who fell ill & were hospitalized.
• Three of the men are suffering a 'handicap that could be irreversible’ and another
has neurological problems.

8. • In particular, neither the French authorities nor Biotrial has
disclosed the identity of the molecule administered in the trials.
Bial did say that the drug was an FAAH (fatty acid amide
hydrolase)inhibitor.
• FAAH is an enzyme produced in the brain and elsewhere in the
body that breaks down neurotransmitters known as
endocannabinoids. By blocking these enzymes, FAAH inhibitors
cause endocannabinoids — which activate the same neural
receptors as the active chemical in cannabis, and might have
painkilling properties — to accumulate in the body.
• Until the Bial clinical trial other pharma companies like Pfizer,
Merck &Co, Sanofi have evaluated FAAH inhibitors as treatments
for pain, mood disorders etc. With no reports of significant ADRs

9. • Neurologist Gilles Edan of the University of Rennes hospital center said that the first patient
from the study arrived on Sunday with very severe symptoms, that Edan's team initially
thought might be caused by a stroke. The patient soon deteriorated further and was brain-
dead. Four other patients have neurological symptoms of varying severity but not in a coma
• 84 people had taken lower doses of BIA 10-2474 in the clinical trial without complications.
• Touraine(Health Minister) said meeting the victims and their families was "a moment of
intense emotion”
• A Bial spokesperson said that she could not comment but that the company would issue a
press statement about the matter later today.
• This study was mixing several goals simultaneously

10. • Le Figaro posted a 96-page clinical study protocol for BIA 10-
2474 that the French newspaper procured from an unnamed
source.
• This Trial is described as 'an accident of exceptional
gravity...without precedence‘
• Problem lies in the fact that health authorities were not informed
in time.
• More upsetting that there is yet no explanation

11. CONCLUSIONS/ACTIONS:-
• This Trial has put to a halt right away, until further investigations.
• Every volunteer who took the drug since the trial began will be
contacted, Marisol Touraine(health minister) said, presumably to
be checked for any adverse events that might have gone
unnoticed.
• Touraine said that prosecutors in Rennes have opened an
investigation and that France's National Agency for Medicines and
Health Products Safety (ANSM) will conduct an investigation as
well. Meeting the victims and their families today was "a moment
of intense emotion“ Touraine said. "The shock is even greater
because people who participate [in phase I trials] are healthy, not
sick, and obviously they don't expect to be confronted with such
accidents.“

12. REFERENCES
• HTTP://WWW.CBC.CA/NEWS/HEALTH/DRUG-TRIAL-FRANCE-
1.3405247
• HTTP://WWW.PHARMEXEC.COM/FRENCH-BIAL-TRIAL-DEATH-
REGULATORS-RELEASE-TIMELINE-EVENTS
• HTTP://WWW.IBTIMES.CO.UK/FRANCE-DRUG-TRIAL-HEALTH-
MINISTER-SAYS-MEDICINE-TRIALS-SHOULD-CONTINUE-DESPITE-
DEATH-1538644
• HTTP://WWW.IBTIMES.CO.UK/FRANCE-DRUG-TRIAL-HEALTH-
MINISTER-SAYS-MEDICINE-TRIALS-SHOULD-CONTINUE-DESPITE-
DEATH-1538644
• HTTP://WWW.BIOTRIAL.COM/NEWS/PRESS-RELEASE-FEBRUARY-
25TH-2016.HTML