- To evaluate the efficacy of pitolisant ( 5, 10, 20,40mg/d in the Double Blind Period and 5, 10, 15, 20, 30, 40mg/d in the Open Label Period) in reducing residual Excessive Daytime Sleepiness (EDS) and the number of cataplectic episodes (for…
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in the intensity and frequency of symptoms of narcolepsy (EDS and
cataplexy) as measured by the Ullanlinna Narcolepsy Scale (UNS) between
baseline: [V1 score (D-14) + V2 score (D0)]/2 and the end of treatment: [V6
score (D49) + V7 score (D56)]/2. We will compare the results between pitolisant
and placebo groups.
Secondary outcome
- Changes in EDS as measured by the maintenance of wakefulness test (MWT)
between baseline and V7, in pitolisant and placebo groups.
- Change in EDS measured by the Paediatric Daytime Sleepiness Scale (PDSS)
between baseline: [V1 score (D-14) + V2 score (D0)]/2 and the end of treatment:
[V6 score (D49) + V7 score (D56)]/2. We will compare the results between
pitolisant and placebo groups.
- Changes in EDS as measured by the Child and Adolescent Sleepiness Scale
(CASS) between baseline and the end of treatment, in pitolisant and placebo
groups.
- Changes in the average number of cataplexy episodes per weeks (recorded in
sleep diary by patient and/or parent/teacher) between the 2 weeks of baseline
and the 2 weeks of end study treatment period (V6, V7), in pitolisant and
placebo groups.
- Differences in weekly frequency of cataplexy episodes (recorded in sleep
diary by patient and/or parent/teacher) between baseline and the 4 weeks of
stable treatment period (V4 to V7), in pitolisant and placebo groups.
- Severity of EDS measured by the Clinical Global Impression of severity and
change. Changes between baseline and V6, V7, in pitolisant and placebo groups.
- Severity of cataplexy measured by the Clinical Global Impression of severity
and change. Changes between baseline and V6, V7, in pitolisant and placebo
groups.
- Changes between baseline and V6, V7 will be compared for the Ullanlina
narcolepsy test, in pitolisant and placebo groups.
- Changes between baseline and V6 will be compared for the TEA-Ch test, in
pitolisant and placebo groups.
- Comparison between placebo and pitolisant groups on:
Withdrawal symptoms questionnaire (DSM IV)
Patients* Global Opinion on treatment effect at the end of treatment if
able to express himself. If not will be reported either by parents or teachers.
- Changes between baseline and at each visit of the open-label period in EDS.
- Safety assessment will be done on monitoring of adverse events, physical
examination, vital signs, ECG and Blood Laboratory tests modifications and the
mood appraisal throughout the study.
Background summary
Pitolisant (BF2.649) is an orally active histamine H3 receptor antagonist /
inverse agonist. After having determined its pharmacological profile showing
that pitolisant enhances the histaminergic transmissions in brain and thereby
improves vigilance, learning and memory and displays pro-cognitive properties,
this product was subject to a number of clinical trials gathering more than 300
adults suffering from narcolepsy with or without cataplexy, and treated by
pitolisant, placebo, or comparator. The results obtained on EDS and on
cataplexy are in favour of BF2.649 (in a statistically significant way with
regard to placebo). Besides, by taking into account all patients who were
administered pitolisant (i.e. 1000 patients in various indications), the safety
profile was proven to be quite satisfactory, thus allowing to envisage the use
of this drug in the paediatric population.
Study objective
- To evaluate the efficacy of pitolisant ( 5, 10, 20,40mg/d in the Double Blind
Period and 5, 10, 15, 20, 30, 40mg/d in the Open Label Period) in reducing
residual Excessive Daytime Sleepiness (EDS) and the number of cataplectic
episodes (for patients with cataplexy)
- To determine safety in children and adolescents
- To assess the long-term safety of BF2.649 in the treatment of EDS in
narcoleptic patients with or without cataplexy.
- To assess the drug-drug interactions with possible concomitant therapies.
- To assess the efficacy of long-term therapy with BF2.649 on EDS after a
prolonged treatment period.
Study design
Double blind, multicentre, randomized, placebo-controlled trial followed by a
prolonged open-label period
Double blind phase of the study:
V0 - Screening visit and start of wash out period (Day-28 = only for patients
under prohibited medications and cataplectic patients under anti-cataplectic
treatment).
V1 - Screening visit and Baseline period (Day -14)
V2 - Randomization and start of escalating period (Day 0)
V3 - Dose adjustment visit (D 14 ± 2 days )
V4 - Dose adjustment visit (D21 ± 2 days )
V5 - Dose adjustment visit (D28 ± 2 days )
V6 - Control treatment visit (D49 ± 2 days )
V7 - End of Double Blind Period (D56 ± 2 days )
T1 - Telephone contact at D59 (± 1 day)
V8 - End of study visit after 1 week of placebo wash out or (D63 ± 2 days ) /
Start of Open label or Premature withdrawal visit (within 5 days after last
treatment intake)
Open-label phase of the study:
Patients completing V8 will have the possibility to continue the treatment with
pitolisant in open conditions until BF2.649 (pitolisant) is available on the
market for children/adolescent from 6 to 17 years.
V9 - Dose adjustment visit (D77 ± 2 days )
V10 - Dose adjustment visit (D84 ± 2 days )
T2 - Telephone contact at D91 (± 1 day )
V11 - Dose adjustment visit (D112 ± 7 days )
V12 - Dose adjustment visit (D196 ± 7 days )
V13 - Dose adjustment visit (D364 ± 7 days )
All subsequent visits are performed each 6 months.
Inclusion period 4 weeks (including 2-week baseline period). Followed by,
Double-blind period, treated by pitolisant or placebo for 8 weeks,
Followed by, Single blind wash-out period, treated by placebo for 1 week and
then Followed by a prolonged open-label period depending on patient wish.
Intervention
The total treatment duration of this double blind study is 8 weeks. Patients
will start pitolisant (or placebo) treatment with escalating doses scheme on
the first 4 weeks, as follows:
- V2 - 5 mg of BF2.649 or placebo / day during the first week,
10 mg of BF2.649 or placebo /day during the second week,
- V3 - Increase to 20 mg/d or maintain at 10 mg/d or reduce to 5 mg/d of
BF2.649 (or placebo) per day for 7 days depending on efficacy and tolerability.
- V4 - It will also be possible to reduce the dose administered to the
patients, or to increase it without exceeding 40 mg/d. Patients with a weight
less than 40kg could be treated with a maximum daily dose of 20mg.
- V5 - It will be possible to reduce the dose administered to the patients, but
not to increase it. As from V5 onwards, no dosage change of the study treatment
will be authorized.
- At the end of the double blind treatment (V7), the investigator will provide
placebo to all patients for the one-week wash out period.
In open-label period patients will start pitolisant treatment with escalating
doses scheme, as
follows:
- V8 - 5 mg of BF2.649 or placebo / day during the first week.
10 mg of BF2.649 or placebo /day during the second week.
- V9 - The third week according to investigator prescription and evaluation on
efficacy and tolerance, the dose will be maintained or increased at 20mg/d or
reduced at 5 mg/d.
- V10 - According to investigator prescription and evaluation on efficacy,
tolerance and weight, the dose will be maintained, reduced or increased at 5,
10, 15, 20, 30 or 40mg/d (only if patient weight is above 40kg) for the next
4-week.
During the phone contact (T2), in opinion of investigator, the dose could be
re-adjusted according to the effectiveness/tolerability of treatment to
patient. In case of need, it is possible to plan a visit on site within the
week following the telephone contact for obtaining new bottles of treatment
with the corresponding dose. The other dose decrease, from 40 to 20 and 10 to 5
mg, in agreement with the investigator don't need to visit. The bottles contain
a suitable number of tablets to decrease the dose.
- V11 - According to investigator prescription and evaluation on efficacy,
tolerance and weight, the dose will be maintained, reduced or increased at 5,
10, 15, 20, 30 or 40mg/d (only if patient weight is above 40kg) for the next
3-month.
- V12 - According to investigator prescription and evaluation on efficacy,
tolerance and weight, the dose will be maintained, reduced or increased at 5,
10, 15, 20, 30 or 40mg/d (only if patient weight is above 40kg) for the next
6-month.
- All subsequent visits, the treatment dispensation will be done like V12.
Study burden and risks
As pitolisant is a new treatment, not all of its adverse effects are known,
although the most commonly observed adverse effects with pitolisant in
comparison with placebo in the previous 25 studies were: insomnia, headache,
nausea, gastric disorders, anxiety, hallucinations, irritability, dizziness,
depression, vomiting, vertigo.
Most of these reported adverse effects were mild or moderate. All these effects
were transient and went away on their own or when the treatment was stopped. In
all 25 clinical trials, no serious side effects durably associated with
pitolisant were observed. There were no serious sequelae following
treatment-related adverse events.
In addition, all treatments carry a risk of an allergic reaction.
Blood sampling is usually well tolerated. Blood is drawn into a small syringe
through a needle inserted into a vein. A mild local reaction at the needle
insertion site may occur. On request, a local anesthetic can be used for the
needle insertion. The amount of the blood sample (5 mL per sample for the
laboratory tests, or a total of 10 mL for the first part of the study) will
have no repercussions on the child*s health.
Possible benefits:
Both phase II and III studies performed in narcoleptic patients with or without
cataplexy, all of them being treated by pitolisant or placebo during 8 weeks
and analysed, confirmed the efficacy of pitolisant on excessive daytime
sleepiness with effects statistically superior to those of the placebo.
In addition, the analysis of sleep diaries completed by the patients during 7
days prior to each visit showed a possible reduction of the risks of cataplexy.
Rue Rameau 9
Parijs 75002
FR
Rue Rameau 9
Parijs 75002
FR
Listed location countries
Age
Inclusion criteria
1) Male and female children from 6 to less than 18 years of age (until V8)
suffering from narcolepsy with or without cataplexy - meeting the International
Classification of Sleep Disorders (ICSD-3) criteria (narcolepsy type 1 and 2).
Diagnosis confirmed with polysomnography and Multiple Sleep Latency Test for
patients without cataplexy (if these examinations were not performed within the
last 12 months), 2) PDSS score >= 15 during baseline period (V1+V2) / 2., 3)
Patients should be free of non-authorized medication, in particular
psychostimulant treatments as from the screening visit (V0) onwards., 4)
Parents - and patients old enough to understand who have expressed a
willingness to participate in the study, who have signed and dated the informed
consent form prior to beginning protocol required procedures., 5) In the
opinion of the investigator, the patient must have adequate support to comply
with the entire study requirements as described in the protocol (e.g.,
transportation to and from trial site, self rating scales and diaries
completion, drug compliance, scheduled visits, tests). , 6) Female pubescent
patients shall use a birth control method, judged efficient by the
investigator, throughout the study and during the month following treatment
discontinuation., 7) Patients should benefit from appropriate healthy insurance
system (only applicable where mandatory e.g. in France).
Exclusion criteria
1) Any other conditions that can be considered the primary causes of EDS: such
as sleep related breathing disorders as defined by a sleep Apnea Index >= 5 per
hour or/and an Apnea/Hypopnea Index >= 10 per hour, chronic sleep deprivation,
circadian sleep wake rhythm disorder or any other medical or neurological
causes that could account for narcolepsy symptoms associated with EDS., 2)
Cataplectic patients treated by anticataplectics (SNRI, SSRI, sodium oxybate)
which are not under a stable treatment since at least 4 weeks at the time of
inclusion (V2). , 3) Patients treated for cataplexy or any other pathology, by
tricyclic antidepressants (clomipramine, imipramine, mirtazapine,
desmethylimipramine and protriptyline) are not authorized because they display
histamine H1 receptor antagonist activity., 4) The use of pitolisant within a
30-day period prior to initial screening visit (V0) for this trial., 5) Current
or recent (within one year) history of a substance abuse or dependence disorder
including alcohol abuse as defined in Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV)., 6) Any significant abnormality of the
electrocardiogram and particularly Fridericia*s QTc interval (QTcF = QT/3*
60/HR) higher than 450ms. , 7) Patients with severe depression (CDI >= 16), 8)
Patient with suicidal risk (C-SSRS) , 9) Positive urinary drug testing (test
applicable to patients from 12 years), 10) Pregnancy (defined as positive β-HCG
blood test), breast-feeding, or patients and unable to use an efficient method
of birth control shall not be included in the study (for pubescent female
only)., 11) Patients with severe hepatic Impairment (Child Pugh C) or with any
other significant abnormality in the physical examination or clinical
laboratory results., 12) Psychiatric and neurological disorders, such as
moderate or severe psychosis or dementia, depression, history of seizure
disorder or other problem that, in the investigator*s opinion, would preclude
the patient*s participation and completion of this trial or comprise reliable
representation of subjective symptoms., 13) Active clinically significant
illness, including unstable cardiovascular, endocrine, neoplastic,
gastrointestinal, haematological, hepatic, immunologic, metabolic, neurological
(other than narcolepsy/cataplexy), pulmonary, and/or renal disease which could
interfere with the study conduct or counter-indicate the study treatments or
place the patient at risk during the trial or compromise the study objectives.,
14) Prior severe adverse reactions to CNS stimulants., 15) Known
hypersensitivity to the tested treatment including active substance and
excipients., 16) The inability to continue daily activities safely, without the
use of treatment against EDS., 17) Any patient presenting congenital
galactosemia, glucose-galactose malabsorption or lactase deficiency due to the
presence of lactose in investigational treatments., 18) Patients participating
in another study or being in a follow-up period for another study., 19) Cannot
be contacted in case of emergency.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001506-29-NL |
| CCMO | NL58537.058.16 |