Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02107079 |
| Other study ID # |
Melaform |
| Secondary ID |
2011-003068-61 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 3, 2014 |
| Last updated |
April 3, 2014 |
| Start date |
January 2012 |
| Est. completion date |
January 2012 |
Study information
| Verified date |
April 2014 |
| Source |
Utrecht University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) |
| Study type |
Interventional
|
Clinical Trial Summary
The circadian rhythm, the sleep-wake cycle, is mainly regulated by melatonin. The synthesis
of melatonin is stimulated by the absence of light, leading to peak serum levels before
bedtime. In humans, this endogenous "signaling" neurohormone induces sleep. Exogenous
melatonin can be beneficial in different sleep disturbances including delayed sleep phase
insomnia, melatonin- deficiency-related insomnia (especially in elderly) and shift work
sleep disorder. Melatonin is known for its low and variable bioavailability in humans due to
a high first pass effect and variable pharmacokinetics and short half-life. In order to
prevent exposure of patients with unnecessary high dosages of melatonin and in order to
achieve a short Tmax and high bio-availability of melatonin, a proper formulation needs to
be defined. This study, a three-phased cross-over study, aims to define a proper formulation
for oral and oromucosal melatonin for the treatment of insomnia by investigating the Tmax
and relative bioavailability derived from melatonin levels in salivary samples of healthy
volunteers after administration of melatonin in different formulations: 2,5mg melatonin
immediate release capsule (produced by Apotheek UMCU), 1mg melatonin immediate release
tablet (produced by Tiofarma), low-dose 0.1mg melatonin original Sleepzz tablet (produced by
Vemedia Manufacturing BV).
Description:
The circadian rhythm, the sleep-wake cycle, is mainly regulated by melatonin. The synthesis
of melatonin is stimulated by the absence of light, leading to peak serum levels before
bedtime. In humans, this endogenous "signaling" neurohormone induces sleep.
Exogenous melatonin can be beneficial in different sleep disturbances including delayed
sleep phase insomnia (Dahlitz et al. 1991, Regestein et al. 1995), melatonin-
deficiency-related insomnia (especially in elderly) (Garfinkel 1995, Etzioni et al. 1995)
and shift work sleep disorder (Folkard et al. 1993, Skene et al. 1996).
A randomized controlled trial of van Geijlswijk et al. (van Geijlswijk 2010) showed that no
relationship could be demonstrated between melatonin dose (0.05-0.15 mg/kg) and shift of
sleep onset time (SOT), shortening of sleep onset latency (SOL) and shift of dim light
melatonin (DLMO). On the other hand, the timing of melatonin administration did have a
clinically and statistically significant effect on all three parameters. Timing of melatonin
administration in relation to baseline DLMO determines the phase advance, as can be measured
by the shift of DLMO and SOT to an earlier time in the evening, resulting also in a shorter
SOL. Melatonin must be administered in a closely defined time-slot before endogenous DLMO
and before bedtime. The phase advance occurs when melatonin is administered 1-2 hours before
DLMO and bedtime (van Geijlswijk et al. 2010). This trial demonstrated that low dosage of
melatonin (0.05mg/kg) is effective in children when given at least 1-2 hours before the
individual DLMO and the desired bedtime. This means that the release of melatonin from any
pharmaceutical formulation should occur fast enough in order to achieve predictive high
levels within the desired time-slot before the occurrence of (baseline) DLMO to induce a
phase advance. These high maximum serum levels shortly after administration (Tmax) means the
release rate of melatonin from the formulation needs to be as fast as possible and the
bioavailability needs to be as high as possible.
Melatonin is known for its low and variable bioavailability in humans due to a high first
pass effect and variable pharmacokinetics and short half-life. In order to prevent exposure
of patients with unnecessary high dosages of melatonin and in order to achieve a short Tmax
and high bio-availability of melatonin, a proper formulation needs to be defined. Thereby,
the bioavailability must be made less variable in order to understand the biologic effects
of melatonin (Di 1997).
Aim/objective. This study, a three-phased cross-over study, aims to define a proper
formulation for oral and oromucosal melatonin for the treatment of insomnia by investigating
the Tmax and relative bioavailability derived from melatonin levels in salivary samples of
healthy volunteers after administration of melatonin in different formulations: 2,5mg
melatonin immediate release capsule (produced by Apotheek UMCU), 1mg melatonin immediate
release tablet (produced by Tiofarma), low-dose 0.1mg melatonin original Sleepzz tablet
(produced by Vemedia Manufacturing BV).
Study-design. Three-phased cross-overstudy. Study-population. The study population will
consist of 10 healthy volunteers (male) aged 18 to 35 years old without insomnia. They will
be recruited in the Netherlands. Intervention. The intervention starts between 10:00 and
11:00 am when the participant flushes his mouth with water, waits 15 minutes and starts to
chew on a cotton plug during 1 minute. Directly after that the participant will administer
one of the IMP's according to the instructions. The tablet and capsule will be swallowed.
The sublingual tablet will be administered sublingual. 10 minutes after administration the
subjects will drink one glass of water and subsequently try to swallow as much liquid
(including saliva), in order to prevent contamination of the saliva sample with the
remaining exogenous melatonin. At 15 minutes, 30 min, 1 hour, 1.5 hour, 2 hours and 3 hours
after oral administration the participant will chew on new cotton plugs during 1 minute.
After administration of the sublingual tablet saliva samples will be collected at 25
minutes, 40 minutes, 60 minutes, 1.5 hour, 2 hours and 3 hours after sublingual
administration. 15 minutes before each sampling the subject will flush his mouth with water.
The cotton plugs with salivary will be preserved in a test-tube in the freezer and will be
analyzed by Ziekenhuis Gelderse Vallei.
Main study endpoint: the Tmax and relative bioavailability of oral and oromucosal melatonin
derived from melatonin levels in salivary samples of healthy volunteers.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness:
This study will burden the participants in a small extent. As mentioned before, melatonin is
well tolerated and is not reported to have a hangover effect. Its rarely occurring side
effects include fatigue, dizziness, nausea, mild drowsiness, hypothermia and headache
(Wagner 1998, Waldhauser 1990, Dahlitz 1991, Garfinkel 1995, Dollins 1994). Besides that,
the participants will be asked to perform simple actions during 3 intervention days for only
3 hours.
The low dose 0.1mg melatonin original Sleepzz table is available without prescription in
drugstores in the Netherlands. The tablet will also contain low dosage of melatonin,
respectively 1mg and the capsule will contain regular dose of melatonin (2,5mg). These
dosages are safe for adults and children. A few reports have been published on the
consequences of long-term treatment with melatonin in humans. (Severe) adverse events were
not described in these reports. (Van Geijlswijk 2011, Jan et al. 1996, Jan et al. 1994,
Gilberg et al. 1997, Smits et al. 2001, Arendt 2000).
