A Phase 1, Open-Label, Single Ascending Dose Study to Evaluate the
Pharmacokinetics and Safety of Solriamfetol in Pediatric Subjects with
Narcolepsy

Narcolepsy is a life-long neurologic disease for which no cure has been
identified. Narcolepsy is commonly diagnosed in adulthood; however, onset
typically occurs in childhood or adolescence. The diagnostic criteria
(International Classification of Sleep Disorders-3 [ICSD-3]; Sateia 2014) for
pediatric patients with narcolepsy (Type 1 and Type 2) are the same as those
used for adult patients. For example, in the multiple sleep latency test
(MSLT), which is part of the diagnostic criteria in both children and adults,
the criteria for a diagnosis of narcolepsy in children is the same as those for
adults: both requiring a mean sleep latency < 8 minutes and * 2 Sleep-onset
rapid eye movement periods (SOREMPs). Children and adolescents with narcolepsy
have been reported to meet these criteria in 92% to 100% of cases across
several studies in pediatric narcolepsy. In addition, the mean number of
SOREMPs in the MSLT was approximately 3 across studies in 150 children and
adolescents, a value similar to that seen in adult MSLT studies (Challamel
1994; Guilleminault and Pelayo 1998). Consistent with findings in adults, the
average sleep latency on the MSLT in children and adolescents is reported to be
< 5 minutes in multiple pediatric studies (Dauvilliers 2001; Huang and
Guilleminault 2009; Aran 2010; Han 2011; Jambhekar 2011; Lecendreux 2012;
Mansukhani and Kotagal 2012; Partinen 2012; Nevsimalova 2013; Poli 2013).
The signs and symptoms of narcolepsy in children are the same as those in
adults. The pentad of narcolepsy symptoms seen in adults (excessive daytime
sleepiness [EDS], cataplexy, hynogogic or hypnopompic hallucinations, sleep
paralysis, and disturbed nocturnal sleep), which are currently described in
ICSD-3 for the diagnosis of narcolepsy (Sateia 2014), are seen in children and
adolescents with similar frequencies to that of adults. All patients have EDS
and many have some or all of the other 4 core symptoms. Children are similar to
adults in that the development of symptoms may progress over time. These data
indicate the strong similarity in narcolepsy presentation between these 2
populations.

The solriamfetol clinical program that led to its approval in the US and on
which the MAA was submitted to the CHMP comprised 18 completed studies in
adults. To date, no PK studies have been conducted with solriamfetol in
pediatric subjects. This phase 1, multi-center, open-label, 3-period,
fixed-sequence, single ascending dose study is designed to characterize the PK
in pediatric subjects, evaluate the safety profile, and to inform dose
selection for future pediatric studies.
Dose selection for this study is based on population PK simulations from adult
PK data and the calculated safety margins from the juvenile toxicology study.
For further details on dose selection, please refer to Section 1.2.4.
Solriamfetol has a systemic elimination half-life of 5.0 to 7.6 hours in
adults; therefore, the washout periods of 14 ± 2 days separating consecutive
dosing Periods are long enough for drug elimination and also for keeping the
blood volume collection within acceptable limits.
No control/placebo group is necessary in this phase 1 open-label study to
evaluate the PK of solriamfetol.
This study was designed in accordance with:
* Regulation (EU) No 536/2014 *Ethical considerations for clinical trials on
medicinal products conducted with minors.*
* The ethical principles given in these guidances, which have their origins in
the Declaration of Helsinki.
* Regulation (EU) No 536/2014 on clinical trials on medicinal products for
human use.
* EU Paediatric Regulation 1901/2006 (as amended by Regulation 1902/2006).

PRIMARY OBJECTIVE To characterize the pharmacokinetics (PK) of single doses of
solriamfetol
in pediatric subjects with narcolepsy.
SECONDARY OBJECTIVE To assess the safety and tolerability of single doses of
solriamfetol in
pediatric subjects with narcolepsy.

This is a phase 1, multi-center, open-label, 3-period, fixed-sequence,
single ascending dose study to evaluate the PK and safety of solriamfetol
in pediatric subjects (6 to < 18 years old) with narcolepsy.
Twelve pediatric subjects who have satisfied all eligibility criteria, 6
subjects in each age group, are planned to be dosed. An attempt will be
made to enroll an equal number of male and female subjects in each
group. Additionally, an attempt will be made to enroll at least 2 subjects
below the age of 9.
The study consists of a Screening Period, which is followed by 3
Pharmacokinetic/Safety Periods, and the End of Study Period.
Screening Period (up to 28 days)
All subjects will undergo screening evaluations to determine their
eligibility within 28 days before dosing. Prior to conducting any studyrelated
screening procedures, all subjects will provide written assent and
their parent(s) or guardian(s) will give written informed consent.
Pharmacokinetic/Safety Periods (approximately 4 weeks)
Each subject in Group 1 (adolescents 12 to < 18 years old) is planned to
receive 3 single oral doses of solriamfetol (ie, 75, 150, and 300 mg)
during 3 separate Periods 1, 2, and 3, respectively, in an ascending
manner. Each subject in Group 2 (children 6 to < 12 years old) is planned
to receive 3 single oral doses of solriamfetol (ie, 37.5, 75, and 150 mg)
during 3 separate Periods 1, 2, and 3, respectively, in an ascending
manner. Periods 1, 2, and 3 will be separated by washout periods of 14 ±
2 days.
Dosing in Group 2 will not start until dosing in Group 1 has been
complete and all the safety, tolerability, and PK data from all
subjects/doses in Group 1 have been reviewed by the principal
investigators (or designee) and Jazz medical/clinical staff. In the event of
observing intolerance or unexpectedly high exposures relative to the
predicted PK exposures at 75 or 150 mg in subjects in Group 1, that dose
and any higher dose if applicable will not be administered in Group 2.
Within Group 1 and Group 2, each subject will be allowed to dose
escalate from Period 1 to Period 2 and from Period 2 to Period 3
independently of other subjects in the same group. Within each age
group, however, not more than 2 subjects can receive the same dose at
the same time. A safety evaluation for each subject will be performed by
the principal investigator (or designee) and Jazz medical/ clinical staff
before the next higher dose can be received.
End of Study Period (approximately 1 week)
At the End-of-Study, which will occur 7 ± 2 days after the last dose was
received at Period 3, subjects will return as outpatients to complete the
End of Study assessments. Subjects who discontinue early should also
return as outpatients to undergo End of Study assessments 7 ± 2 days
after receiving their last dose.

Each subject in each age group will receive 3 single oral doses of solriamfetol
(if tolerated) during 3 separate periods, in an ascending manner (Table 1).
Dosing in Group 2 (children 6 to < 12 years old) will not start until the
dosing in Group 1 (adolescents 12 to < 18 years old) is complete.
Within Group 1 and Group 2, each subject will be allowed to dose escalate from
Period 1 to Period 2 and from Period 2 to Period 3 independently of other
subjects in the same group. Within each age group, however, not more than 2
subjects can receive the same dose at the same time. A safety evaluation for
each subject will be performed by the principal investigator (or designee) and
Jazz medical/clinical staff before the next higher dose can be received for
each subject.
In performing these safety evaluations as each subject dose escalates from a
lower to a higher dose, the principal investigator (or designee) and Jazz
medical/clinical staff will review each subject*s safety data in alignment with
the known safety profile of solriamfetol. The safety data will include, but not
be limited to, vital signs, ECGs, C-SSRS, and AEs. Once each safety review has
concluded that adequate safety and tolerability have been demonstrated, each
subject will be permitted to proceed to the next higher dose.
Once the last subject in Group 1 has completed the last study period, PK will
be assessed for all subjects in this group. The safety, tolerability, and PK
data from all subjects/doses in Group 1 will be reviewed by the principal
investigators (or designees) and Jazz medical/clinical staff before dosing can
begin in Group 2.
Within Group 1, dosing will be terminated at any dose, and any higher dose if
applicable, if 3 or more subjects at that dose:
* Had a drug-related serious adverse event (SAE), or
* Had a drug-related nonserious adverse event (AE) of severe intensity
requiring medical intervention.
If dosing is terminated for the 75 mg dose in Group 1, subjects in Group 2 will
still receive the 37.5 mg dose. If dosing in Group 1 is terminated at 150 mg,
subjects in Group 2 could still receive the 37.5 and 75 mg doses.
Furthermore, in the event of observing unexpectedly high exposures relative to
the predicted PK exposures at 75 mg in subjects in Group 1, the 75 and 150 mg
doses will not be administered in Group 2. If unexpectedly high exposures
relative to the predicted PK exposures are only observed at the 150 mg dose in
subjects in Group 1, the 150 mg dose will not be administered in Group 2.
Within Group 2, dosing will be terminated at any dose, and any higher dose if
applicable, if 3 or more subjects at that dose:
* Had a drug-related SAE, or
* Had a drug-related nonserious AE of severe intensity requiring medical
intervention.
Table 1 Treatment and dosing schedule
Age Group Period 1 Period 2 Period 3
Group 1,
12 to < 18 years old
(N = 6) 75 mg 150 mg 300 mg
Group 2,
6 to < 12 years old
(N = 6) 37.5 mg 75 mg 150 mg

The washout period (ie, 14 ± 2 days) was selected in consideration of keeping
the blood volume collection within the acceptable limits as advised by the
applicable guidance (eg, the European Commission*s recommendations *Ethical
considerations for clinical trials on medicinal products conducted with
minors*, 2017 or according to IRB/EC guidelines). For example, the 2017
guidance specifies that the volume of blood taken on any 1 occasion should not
exceed 1% of the total blood volume and the blood volume taken in any 4-week
period should not exceed 3% of the total blood volume.
Subjects will check into the study site the evening of Day -1 (Period 1) and
will remain at the study site for approximately 10 hours after receiving their
dose on Day 1 for PK and safety assessments. Subjects will receive a single
dose of solriamfetol as a tablet with 240 mL of water in the morning
approximately 2 hours after completing a light breakfast, which will be
provided at the study site. The contents of the light breakfast should be of
the same or similar content on each day blood is drawn for PK assessment.
All subjects will return to the study site 2 additional times (Period 2 and
Period 3) for PK and safety assessments (see Appendix A). At these visits,
subjects will receive the next higher dose of solriamfetol, provided that the
prior dose was well tolerated as established by the principal investigator (or
designee) and Jazz medical/clinical staff.
During Periods 1, 2, and 3, blood samples for PK analyses will be collected at
predose and at 1, 2, 3, 6, 8, and 10 hours following administration of the
single dose of solriamfetol. An indwelling catheter may be used to facilitate
the collection of the blood samples.

Solriamfetol has a large adult clinical safety database comprised of healthy
subjects and subjects with OSA, narcolepsy, or MDD with a consistent safety
profile across conditions. The robust wake promoting efficacy of solriamfetol
has been demonstrated among subjects with OSA or narcolepsy.
This study will be conducted in pediatric subjects with narcolepsy. Benefits to
the subjects include a physical examination, clinical safety assessments, and
comprehensive laboratory evaluations. The subjects will also have the
opportunity, if eligible, to participate in future efficacy and/or long-term
solriamfetol safety studies as approved under the pediatric investigational
plan. However, subjects likely will not benefit from taking solriamfetol
directly in the current study as they will be receiving a single dose rather
than maintenance dosing.
Risks to the subjects include those related to solriamfetol and to blood
collection. The risks to subjects are expected to be similar to those seen in
prior clinical studies, which are summarized in Section 1.2.1.2. Adverse events
following a single dose have generally been transient and mild to moderate.