Efficacy and safety of hydralazine in combination with valproate to treat hypocretin deficiency in recent onset narcolepsy: a pilot study

Narcolepsy with cataplexy (also called narcolepsy type 1 or NT1) is a severe
and limiting sleep disorder characterized by excessive daytime sleepiness and
cataplexy (loss of skeletal muscle tone triggered by strong emotions). The best
biological marker of the disease is hypocretin (HCRT) deficiency. Two active
HCRT peptides are known: HCRT-1 and -2. HCRT-1 levels are measured in the
cerebrospinal fluid (CSF) and is typically < 40pg/ml in NT1. Hypocretin
deficiency can be caused by either neuronal death or absence of hypocretin
production. We hypothesized that HCRT deficiency may be caused by epigenetic
silencing of HCRT neurons. To test our hypothesis, we have evaluated the
promoter methylation of HCRT in DNA extracts from lateral hypothalami of 7 NT1
and 7 control subjects.
Our results strongly suggest that an epigenetic silencing instead of HCRT
neuronal loss might cause narcolepsy. Since promoter methylation is a
reversible process, we propose to perform a pilot clinical trial to treat NT1
patients with epigenetic agents. The combination of hydralazine with valproate
has shown clinical efficacy in myelodysplastic syndrome, cutaneous T-cell
lymphoma, and in combination with chemotherapy or radiation against several
solid tumors.

Primary objective:
To assess whether hydralazine in combination with valproate is effective in
treating the symptoms of narcolepsy.
Secondary objectives:
- To assess the safety of treating NT1 patients with hydralazine in combination
with valproate.
- To assess whether the efficacy of hydralazine in combination with valproate
is reflected in an increased concentration of hypocretin-1 in the CSF.

Open-label pilot-study in 8 patients with recent onset NT1 (< 5 year after
symptom-onset). Included NT1 patients will receive the combination of daily
oral hydralazine and valproate for 6 weeks.

Included patients will receive 25-50mg of hydralazine 3 times daily and 30mg/kg
of valproate divided in 2 dosages daily for 6 weeks.

Subjects might potentially directly benefit from participating in this study,
if our hypothesis were true. Demethylating HCRT gene promoters in cells capable
of producing HCRT might reverse the disease process and may lead to a
sustainable improvement of narcolepsy symptoms.

Treatment
Both hydralazine and valproate are approved medications for the treatment of
hypertension and epilepsy, respectively. There is long time experience with
both substances and risks are limited and well-known (see also D1-2); the
researchers have ample experience prescribing valproate for the treatment of
epilepsy. There is no known interaction between both types of medication.
Moreover, hydralazine will be used in a lower dosage than usually prescribed
for hypertension.
Side effects of both valproate and hydralazine are described in D1-2. Severe,
but rare side effects of valproate include liver and pancreatic damage/failure
(especially with mitochondrial enzymal defects in young children) and
teratogenicity. However, these side effects are very rare in adults. In our
study, laboratory and pregnancy tests are used to assess liver function and to
exclude pregnancy. Female subjects could only be included if they use an
effective contraceptive method.
Noteworthy side effects of hydralazine include a lupus erythematodes-like
syndrome (which could be treated by corticosteroids) and hypotension (treated
by slowly discontinuing hydralazine to prevent hypertension when withdrawal is
too abrupt). In this study, assessing acetylation-status is performed to
diminish the chance of these side effects to appear.

Laboratory tests
The drawing of blood may cause pain and/or bruising; fainting may occur during
or shortly after the intervention. If so, the subject will be instructed to lie
down immediately.

PSG and MSLT
A minor burden consists of one night of PSG measurements and one MSLT day.
Apart from the time investment, PSG and MSLT are non-invasive and are generally
not considered bothersome by patients undergoing these procedures.

Lumbar puncture
The drawing of CSF by lumbar puncture (which will be performed only in those
subjects with a substantial improvement of narcolepsy symptoms) may cause pain.
Subjects are already in a horizontal position, which decreases the risk of
fainting. A common side effect is headache due to the dural punction (10-30%).
In rare cases, a postpunctional hypoliquorrhoe syndrome develops for which it
is necessary to provide a second puncture and inject a small amount of the
subject*s blood (blood patch) to close the dural gap.