Effects of acute and chronic oral administration of S 44121 versus placebo on cardiac arrhythmia during exercise testing in patients with catecholaminergic polymorphic ventricular tachycardia type 1 - A randomized, parallel-group, international multicentre study including a 8-week double-blind placebo controlled period followed by a 8-week single-blind period - Phase II exploratory study

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially
lethal disease characterized by adrenergically mediated ventricular
arrhythmias. CPVT is one of the most severe inherited arrhythmogenic disorders
and is the most lethal ion channel-associated cause of sudden cardiac death.
The prevalence of the disease is estimated to be 1:10,000 in Europe (Orphanet,
2011).
At present, no treatment is available to cure the condition, but treatments
aimed at the prevention or termination of cardiac arrhythmias upon activation
of the sympathetic nervous system are available. Beta-blockers are the mainstay
of treatment for these patients, and are uptitrated on an individual basis upon
tolerability and control of arrhythmias during exercise testing. Periodic
re-evaluation of beta-blocker efficacy is performed on the basis of exercise
testing performed at the highest tolerated workload. Despite an individually
optimised treatment regimen, the protection against cardiac arrhythmias often
remains incomplete and many continue to have symptoms and/or documented
exercise-induced ventricular arrhythmias. In these cases, an implantable
cardioverter-defibrillator (ICD) is the currently recommended treatment option.
Given the mortality risk and the incomplete protection with current therapies,
a high medical need exists for these patients. The disease-causing gene in CPVT
type 1 is the ryanodine receptor 2 (RyR2) gene. The gene codes a ryanodine type
2 channel (RyR2), which has a major role in the intracellular calcium handling
in the cardiac muscle. The new investigational compound S 44121, a
benzothiazepine derivative, acts as a ryanodine receptor modulator and can
improve the rebinding of calstabin-2 to hyperphosphorylised RyR2 channels.
Therefore, this compound may be of use in patients with CPVT type 1.
Up to now, S 44121 was administered to a total of 165 healthy volunteers, by
the oral or intravenous route. Overall, S 44121 presented a good safety
profile. No serious adverse events, biological abnormalities, or
electrocardiogram (ECG) abnormalities were reported (Clinical investigator*s
brochure, 2011) . A phase II exploratory study has been performed to assess the
effects on cardiac arrhythmia of three single oral administrations (500, 1000
and 1500 mg) of S 44121 during exercise testing in patients with CPVT type 1
(n=14 patients). Preliminary results show an efficacy in terms of reduction of
PVCs per minute in around 30 % of the patients and a good safety profile. No
serious adverse events have been reported and all patients have completed the
study. The compound is also currently assessed in chronic heart failure and up
today 180 patients have been treated up to 3 months at doses from 250 to 1000
mg b.i.d.. The possible side effects after oral administration are those
related to the alimentary tract such as nausea and abdominal pain.
Overall, in view of the preclinical and clinical data showing an
anti-arrhythmic efficacy and a good tolerability profile, the benefit-risk
balance is considered favourable (Clinical investigator*s brochure, 2011)
regarding the proposed study.

The objective of this study is to assess the effects of a single and chronic
oral administration of S 44121 versus placebo on the occurrence of cardiac
arrhythmia during standardized exercise tests (ETs) in patients with CPVT type
1. The safety profile of S 44121 will also be evaluated.

This study is a phase II, parallel-arm randomised multicentre international
exploratory study including a 8-week double-blind placebo controlled period
followed by a 8-week single-blind period. The study will be performed in
approximately 36 patients with CPVT type 1 .
The total duration of the study per patient is maximum 18 weeks.
Study plan: see protocol pag 19 (fig 8.2.1)

S44121 (dosis 250 - 500 - 1000 mg) and placebo, treatment taken twice daily
period of 8 weeks double blind, followed by a period of 8 weeks single blind
visits:
- preselection visit (Pre-SEL): confirmation of the diagnosis of CPVT
- selection visit (SEL): 2 qualification exercise tests (ETs)- start run-in
treatment with single blind placebo, twice a day
- inclusion visit (W000): 1 to 14 days later- start double blind treatment:
S44121or placebo, twice a day
duration of 8 weeks double blind period with visits on W004 en W008
- 4 weeks single blind period between W008 en W012: S44121 dosed at 1000mg ,
twice a day
- single blind periode(1-4 wks) till vist W016: placebo, twice a day

The patient will have to perform the following procedures for the study:
- Exercise testings (ETs): 2 (to 3) at the selection visit to determine the
qualification of the patient to continue the study. The first ET will have to
start 2 hours after the betablocker intake, the second ET again 2 hours later.
This is time consuming for the patients. At inclusion, visit week 4 - 8 - 12 -
16 , 1 ET will have to be performed. The patient will have to bicycle around 10
minutes, depending on his physical condition, during which an ECG is taken. The
final duration will be decided by the patient or the investigator. All ETs will
be performed under strict medical supervision. The results of the standardised
ETs are used to evaluate the primary endpoint of the study.
- 24hours Holter monitoring. Minimal burden for the patient. A Holter will have
to be performed at inclusion and at visit of week 8. At the visits of week 4
and 12 it is optional.
- Bloodsamplings for analysis of hematology and biochemistry: this will have to
be performed fasting, at inclusion, and the visits of week 8 - 1 2 -16. The
bloodsamplings need to be taken fasten because food intake can influence
certain parameters (blood glucose, cholesterol) and have an impact on the
results .
- Blood samplings for pharmacokinetic analysis (at week 4 - 8 - 12). These are
more time consuming for the patients. At week 4 the third blood sampling needs
to be performed 4 hours after study medication intake, and at week 12, 3hours
later. The patient will receive some compensation for the visits with a stay of
more than 3 hours in the hospital. When several samplings need to be performed
during the same visit, the physician can place a catheter during the duration
of the study to facilitate the blood draws and avoid repetitive punctures.
In total a maximum of 100ml blood will be sampled during the whole study
duration of 18 weeks.
- Blood sampling for pharmacogenetic anaysis: participation is optional (needs
to be approved by the patient): to be done at week 4.
- Skin biopsy (once): participation is optional (needs to be approved by the
patient). The skin is anesthesised locally and a small part is excised (not
more than the tip of a pen), often at the lower back. Some burden can be
experienced by the patient. The major risks are rare.
Up to now, S 44121 was administered to healthy volunteers and patiens with
chronic heart failure at similar doses up to 3 months. In patients with CPVT
S44121 was adminstered during 2 days and the medication was well tolerated. The
possible side effects of S44121 are those related to the alimentary tract such
as nausea, indigestion and abdominal pain. Other side effects and burden can
appear that are unknown until now and that can not be predicted well at this
moment.

The safety of the study patients is verified during the study by the DSMB. On
10/10/2012, 5 patients were included in this study internationally. One of
these patients experienced a ventricular fibrillation 2 days after first study
drug administration and was withdrawn from the study. After thorough evaulation
of this case as well as of the data of other ongoing studies with S44121, the
DSMB has decided the trial can continue to safely include patients if patients
have an implanted ICD. Following this decision the protocol has been amended
accordingly.