Rhizomelic Chondrodysplasia Punctata Clinical Trial
Official title:
A Prospective Natural History Study of Patients With Rhizomelic Chondrodysplasia Punctata (RCDP)
A prospective, longitudinal observational trial in patients with RCDP. Study participants will be evaluated at baseline and approximately every 6 months by the study team. Quality of life, physiologic and functional measurements will be performed. In addition, audiologic recordings and other surveys will be completed at home by parents beginning at baseline and every 3-6 months thereafter.
Rhizomelic chondrodysplasia punctata (RCDP) is a group of rare diseases that have no known
cure. It is a genetic disorder characterized by mutations in the Peroxisomal Biogenesis
Factor 7 (PEX7) gene (RCDP1), Glyceronephosphate O-acyltransferase (GNPAT) gene (RCDP 2),
Alkylglycerone phosphate synthase (AGPS) gene (RCDP3), Fatty Acyl-CoA Reductase 1 (FAR1) gene
(RCDP4) or Peroxisomal Biogenesis Factor 7 (PEX7) gene (RCDP5) all coding for peroxisomal
proteins which result in defective synthesis of plasmalogens. Hence, severely decreased
levels of ethanolamine plasmalogens (PlsEtn), the most common tissue plasmalogen, is both the
biochemical hallmark and the primary cause of pathology for all RCDP groups. To treat RCDP, a
plasmalogen replacement is under development. Before this therapeutic or any therapeutic for
RCDP can be tested for efficacy in the clinic, a thorough understanding of the natural
progression of the disease is required. Without this information it would be impossible to
determine whether the drug was effectively improving the disease course. Classical, or
severe, is the most common form of RCDP and presents in the neonatal period. It is clinically
characterized by a skeletal dysplasia as seen by symmetrical rhizomelic shortening of the
long bones. Chondrodysplasia is also present with premature calcification of epiphyseal
cartilage (punctata), delayed calcification of vertebral bodies and mineralization of
cartilaginous structures which do not normally ossify, such as the larynx, trachea and
intervertebral discs. Additionally patients display dysmorphic facial features, bilateral
cataracts, cognitive deficits and severe growth and psychomotor delays. Shortened life
expectancy is common to RCDP patients; however survival varies widely. For the classical
form, of those individuals who survive the first month of life, 50% will survive until 6
years of age with nearly all succumbing to the disease by adolescence. The majority of deaths
are secondary to respiratory problems5. The chronic respiratory compromise is due to the
skeletal defects, as well as the direct effect of plasmalogen deficiency on lung cellular
function. Patients with less severe phenotypes can lack rhizomelia, and have less severe
growth and developmental delays. The disease phenotype varies considerably and correlates
directly with PlsEtn abundance.
STUDY RATIONALE Determining the appropriate measurable endpoints are as important as having a
viable therapeutic strategy for a clinical trial. In a disease like RCDP, endpoints must be
sensitive enough to measure subtle changes in the course of the disease and also be
meaningful to the process of pathogenesis. Assessment of a RCDP treatment trial is a complex
task as RCDP clinical trajectory might be influenced by the disease severity, age and care
that the patient receives etc. Moreover, although measurement scales exist for such diseases
as Cerebral Palsy to assess the severity of the disease, RCDP does not have such universally
accepted overall set of measures that assess patient's developmental, functional,
psychosocial, neurological, skeletal, and respiratory functions as a whole. Lack of such
grading scales is a hindrance to evaluate the progress of a clinical trial in a complex and
severe disease as RCDP. In a disease like RCDP, more than a complete cure, a functional
improvement in patient's life could be considered as efficacious.
The other issue in a rare disease clinical trial design is the comparator to which the effect
of treatment can be compared. Ethical considerations preclude having a placebo control and a
more appropriate comparator is a non-concurrent control group. Therefore, longitudinal
assessments are required to determine the inherent variability in functional measures and
characterize the disease trajectory. To this end, we have designed an on-going longitudinal
observational trial with assessments every 3-6 months to characterize RCDP and its disease
course.
Overarching goal is to determine the longitudinal and natural trajectory of disease state in
patients with RCDP by assess the quality of life, physiologic and functional measures.
Specific measurements will include:
- Medical and surgical history
- Anthropometric measurements
- Vital signs
- Physical examination
- Observational pain assessment
- Musculoskeletal system assessment
- Nerve conduction studies
- Non-invasive pulmonary function tests
- Impulse Oscillometry System
- Pneumotachography
- Respiratory Inductance Plethysmography
- 4 hour EEG
- DEXA
- Questionnaire assessment of:
- Iowa Fatigue Scale
- Pediatric Pain Scale
- NCCPC-R (Pain Scale)
- Infant Gastrointestinal Symptom Questionnaire
- Pediatric Assessment Scale for Severe Feeding Problems
- LENA
- Parental written logs (over 2 days)
- Activity
- Pain
- Seizure
- Blood Assessments
- Plasmalogen and Lipids
- Complete Blood Count
- Comprehensive Metabolic Panel
- Genetic Testing (if not available from history)
STUDY DESIGN
As described above, clinical characteristics of RCDP encompass a wide range of signs,
symptoms, physiological, functional and structural abnormalities all of which must be taken
in to account when assessing a patient's progress. The major systems affected are the
skeletal system (severe and symmetrical shortening of proximal long bones, stippled
epiphyses, dysmorphia and contractures), neurophysiological (seizures), neuromuscular and
psychomotor abnormalities, respiratory, growth and developmental and daily function. Many of
these symptoms can be characterized by standard tests that are in clinical or research use.
Other assessments, such as the quality of life, require the development of novel tools which
will be implemented once they have been validated. Assessing each domain in its own right
will provide the best indication of efficacy on an individual basis.
Domain specific milestones as described here will increase the sensitivity in assessing
treatment specific effects. Acute clinically evident improvements brought about by
plasmalogen replacement therapy are expected to be subtle. The earliest improvements are
anticipated to be improvements in membrane-related functions such as improved
neurotransmission, improved neuromuscular function, improved GI function, increase growth
rates and better lung health. Functionally, we anticipate that primary and immediate
improvements will be evident in motor function, frequency of seizures, frequency of pulmonary
infections and improved quality of life. Improvements in other systems and function are
anticipated to arise later in a gradual manner. Consequently, assessment of each of these
domains as well as an assessment of quality of life and measures of functionality are needed
to estimate therapeutic benefits accurately.
The study is intended to be on-going, allowing for longitudinal assessment of RCDP. In-
hospital assessments will be completed approximately every 6 months, based on availability of
scheduling and patients' health. In home audiologic recordings will take place after each
study visit along with parent completed logs. In home surveys will be distributed every 3
months to the caregiver.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT05969977 -
A First-in-Human Phase 1 Study of Plasmalogen Precursor PPI-1011 in Healthy Adult Volunteers to Assess Safety, Tolerability, and Pharmacokinetics
|
Phase 1 |