The primary objectives are: 1) to obtain in vivo pharmacokinetic data of 4*-PPT (the study product) measured in plasma of PKAN patients; 2) to obtain pharmacodynamic data of the biomarker COASY in circulating lymphocytes of PKAN patients, when 4*-…
ID
Source
Brief title
Condition
- Iron and trace metal metabolism disorders
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main study parameter/endpoint:
1) 4*-PPT will be measured in the collected blood samples (collected at 10 time
points, according to Table 1).
2) COASY biomarker mRNA expression levels measured in lymphocytes extracted
from blood at 10 time points during the study.
Secondary outcome
Secondary study parameters/endpoints:
1) Safety outcome measures will include study product-emergent adverse events
and abnormalities on routine laboratory tests collected at 10 time points over
2 years of the study.
2) In addition, at 6 time points during the study video recordings will be
performed to objectively measure the neurological examination.
3) Tolerability outcomes will be assessed via participant retention in the
study and adherence to the study product regimen.
Background summary
Pantothenate kinase-associated neurodegeneration (PKAN) is an ultra-rare
neurodegenerative disease affecting children and adults, with a prevalence of 1
case per 1-3 million in the general population. Patients suffer from
progressive generalised dystonia, parkinsonism and brain iron accumulation. The
progression of PKAN is relentless but unpredictable and variable between
patients. No treatment exists for this painful, disabling and fatal disease.
PKAN patients lack an enzyme required for biosynthesis of coenzyme-A, an
essential metabolic co-factor. We have compelling preclinical evidence that 4*-
PPT completely rescues the disease phenotype in PKAN animal and human cell
models. Preclinical studies also identified a promising biomarker. In the long
term we hypothesise that 4*-PPT will slow or stop disease progression in PKAN
patients. It is currently unknown whether 4*-PPT, which is normally not
present in plasma, can be detected in a dose dependent manner in plasma of PKAN
patients when it is orally provided. Our study aims to collect for the first
time in vivo pharmacokinetic information of 4*-PPT, when orally provided, in
PKAN patients. Based on preclinical and limited clinical data we hypothesize
that 4*-PPT will be detectable in plasma of PKAN patients after several days
when daily orally provided.
We propose a within-subject dose-escalation study, investigating 3 subsequent
increasing doses during 5 months followed by an open label extension study of
19 months on the middle dose.
Study objective
The primary objectives are:
1) to obtain in vivo pharmacokinetic data of 4*-PPT (the study product)
measured in plasma of PKAN patients;
2) to obtain pharmacodynamic data of the biomarker COASY in circulating
lymphocytes of PKAN patients, when 4*-PPT is provided daily at 3 subsequent
increasing doses (7,5 mg/m2, 15 mg/m2 and 30 mg/m2) for a month each;
3) to collect data regarding plasma levels of CoA-Z and 4) the biomarker COASY
when 4*-PPT has been orally provided over a period of 19 months on a fixed
dose. We will start a fixed dose of 15 mg/m2 as the default dose, but may
adjust to the lower or higher dose based on the biomarker measurements obtained
from the dose-escalation phase.
The secondary objectives are:
1) To assess safety and tolerability of the used doses of 4*-PPT in PKAN
patients when 4*-PPT is orally provided;
2) Objective neurological examination (video) .
Study design
The proposed trial is a single-center study in which patients receive an
initial daily dose of 7,5 mg/m2 4*-PPT during one month (M0), followed by a
wash-out period of one month (M1). Subsequently a dose of 15 mg/m2 will be
provided (one month; M2), a washout will follow (one month; M3) and finally a
dose of 30 mg/m2 (one month; M4) will be provided. This dose-escalation phase
will be followed up by an open label extension phase of 19 months on a fixed
dose. The default dose will be a daily dose of 15 mg/m2. This dose may be
adjusted per patient, based on the biomarker results obtained in the
dose-escalation phase.
Intervention
All patients will be given 4*-PPT. Patients will be assigned a daily dose of 4*-
PPT, which will be provided in the form of capsules. The content will be
dissolved in water and the desired amount will be orally administered or via
gastronomy tube.
Patients will be visited at home or at a nearby location 10 times during the
first 5 months (M0-M4) of the dose-escalation phase. During the extension stud,
1 visit after 1 year will occur and 1 visit at the end of the trial. Blood
collection will occur at 10 visits for 4*-PPT and COASY, plus routine safety
laboratory tests. A standard video-recording will be taken at 6 of the visits
(visit 2, after each period of increased dose, after 1 year and at the last
visit) to monitor the neurological status of the patient, and regular telephone
contact will occur between the visits as needed.
Study burden and risks
All PKAN patients participating in the study will receive 4*-PPT. Results from
unpublished clinical studies show that 4*-PPT is well tolerated and no side
effects are reported. However, we cannot 100% exclude that the study product
poses risks, when taken over an extended period. All clinical procedures
involved in this research (blood draws and neurological evaluation using video
recording) are judged to pose minimal risk to even the youngest of
participants.
Previous trials in this patient group have showed that traveling, for instance
to the hospital, is a stressful event for patients, not only putting them at
medical risk by increasing neurological symptoms, but also potentially
confounding the study results. Therefore, during the proposed trial, the
clinician will travel to the patients instead of patients traveling to the
clinic and all study procedures including the consent process for the study
will be performed at the residency of the patients. This approach was important
for ZonMw to commit funding for the study. In previous international trials
Dutch PKAN patients were never able to participate. Here for the first time,
they will have access to a possibly lifesaving treatment.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
1. Have a diagnosis of PKAN confirmed by genetic testing showing two pathogenic
mutations, OR one found mutation and typical clinical and imaging features of
the disease.
2. aged >12 months at the time of screening.
3. Be able to take the study product by mouth or via gastrostomy tube.
4. Informed consent is provided by the patient and/or parents, and/or legal
representative.
5. Be resident in The Netherlands or Belgium for the duration of the trial.
6. Have a valid Dutch or Belgian health insurance.
Exclusion criteria
1. subjects must NOT have been exposed to a putative PANK2 *bypass* therapeutic
agent in the 30 days prior to screening.
2. subjects must NOT be concurrently enrolled in another interventional
clinical trial.
3. subjects must NOT have concurrent medical or other conditions that in the
opinion of the investigators are expected to preclude completion of study
procedures or confound the assessment of clinical and laboratory measures of
safety.
4. subjects must be able to understand Dutch.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL73850.000.20 |