The primary objective of this study is to compare respiratory muscle strength values obtained using volitional techniques with values obtained using non-volitional techniques. The secondary objective is to compare the change for these two sets of…
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Brief title
Condition
- Muscle disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to compare respiratory muscle strength
values obtained using volitional techniques with values obtained using
non-volitional techniques
Secondary outcome
The secondary objective is to compare the change for these two sets of values
after 24 weeks in subjects treated or not treated with BMN 701.
Background summary
Progressive respiratory failure is the most frequent cause of death in
late-onset Pompe disease. The Phase 1/2 study (POM-001) of BMN 701 treatment
with 20 mg/kg every other week resulted in substantial improvement in maximal
inspiratory pressure (MIP) and maximal expiratory pressure (MEP) as well as
improvement in other measures of respiratory function and in 6-minute walk test
(6MWT) distance. As a result, a Phase 3 study (701-301) was undertaken to
determine whether BMN 701 can improve measures of respiratory muscle strength
in late-onset Pompe disease patients previously treated with commercial
recombinant human GAA (rhGAA). The primary endpoint of the Phase 3 study is
MIP; one of the secondary endpoints is MEP; one of the exploratory endpoints is
sniff nasal inspiratory pressure (SNIP).
Given that MIP, MEP, and SNIP, like other measures of respiratory strength or
function, depend on the patient making his/her best effort, it is possible
these values may increase through factors other than improvement in respiratory
muscle contractility. Such factors may include subject aptitude, motivation,
cooperation, or practice. Therefore, to substantiate improvement in
effort-dependent test results following BMN 701 treatment in Study 701-301,
this study (701-201) will use the non-volitional technique of magnetic nerve
stimulation to measure diaphragmatic muscle strength to compare with volitional
techniques to measure respiratory muscle strength.
Magnetic nerve stimulation involves a rapidly changing magnetic field emanating
from a coil placed on the skin that simultaneously depolarizes bilateral
phrenic or thoracic nerve motor axons, causing a brief maximal diaphragmatic
contraction, termed a *twitch.* Twitch magnitude is measured as a
transdiaphragmatic pressure (TDP). Measuring diaphragmatic twitch pressure
(TwPdi) and twitch gastric pressure (TwPga) via esophageal (Poes) and gastric
(Pga) pressure balloons provides an objective (effort-independent) measure of
treatment effect.
To assure accurate assessment of respiratory muscle strength, which varies with
lung volume, this study will assess lung volume by whole-body plethysmography.
Because respiratory muscle weakness may compromise gas exchange, this study
will measure the carbon monoxide transfer factor (TLCO) to determine the lung*s
ability to transfer a tracer gas, carbon monoxide, from alveolus to blood
stream. To evaluate BMN 701 treatment effect more comprehensively and to
correlate findings with MIP, MEP, and SNIP measurements in Study 701-301,
respiratory measures also will include MIP, MEP, SNIP, sniff esophageal
pressure (Poes), sniff diaphragmatic pressure (Pdi), and cough gastric pressure
(Pga). To assess ease of lung inflation, this study will measure dynamic lung
compliance, the ability of alveoli and lung tissue to expand during
inspiration. Phrenic and thoracic nerve stimulation will provide
effort-independent respiratory muscle strength by measuring diaphragmatic TwPdi
and TwPga via esophageal and gastric pressure balloons, respectively.
To optimize enrollment for a meaningful comparison of volitional and
non-volitional tests of respiratory muscle strength in patients with late-onset
Pompe disease (primary objective), the study population may include subjects
enrolled in Study 701-301 (switched from commercial rhGAA to BMN 701), subjects
enrolled in Study POM-002 (receiving BMN 701), Study 701-901 (untreated or
receiving commercial rhGAA), and/or late-onset Pompe disease patients enrolled
in no other study (untreated or receiving commercial rhGAA). Change in these
test results after 24 weeks (secondary objective) in subjects not receiving BMN
701 (whether receiving commercial rhGAA or not) will reflect the natural
history of the disease in terms of volitional and non-volitional measures.
Studies POM-002 (N=22), 701-901 (N=100), and 701-301 (N=50) are studies in
patients with late-onset Pompe disease. Study POM-002 is an extension of
POM-001 to evaluate longer-term BMN 701 safety and preliminary efficacy. Study
701-901 is a prospective, noninterventional, observational study in adults
treated or untreated with commercial rhGAA. Study 701-301 is a Phase 3 study of
BMN 701 safety and efficacy in patients switched from commercial rhGAA to BMN
701.
Study objective
The primary objective of this study is to compare respiratory muscle strength
values obtained using volitional techniques with values obtained using
non-volitional techniques. The secondary objective is to compare the change for
these two sets of values after 24 weeks in subjects treated or not treated with
BMN 701.
Study design
Following informed consent, approximately 5 to 15 subjects will enter this
single-arm respiratory study at sites specializing in respiratory assessment.
The study will test respiratory muscle strength initially and again after 24
weeks in subjects treated or not treated with BMN 701 by effort-dependent and
effort-independent techniques. Phrenic and thoracic nerve stimulation will
provide effort-independent (non-volitional) respiratory muscle strength by
measuring diaphragmatic TwPdi and TwPga via esophageal (to obtain Poes) and
gastric (to obtain Pga) pressure balloons.
This study consists of two visits and a follow-up:
* First Visit is after study entry criteria are met. For subjects enrolled in
Study 701-301, the First Visit is after all Study 701-301 entry criteria are
met and before the Week 4 infusion.
* Last Visit
* is 24 ±3 weeks after the First Visit.
Follow-Up
Pulmonary measures at each study visit will include lung volume by whole-body
plethysmography (unless precluded by mobility issues), carbon monoxide gas
transfer, volitional measures of respiratory muscle strength (MIP, MEP, SNIP,
sniff Poes, sniff Pdi, and cough Pga), non-volitional measures of respiratory
muscle strength (TwPdi and TwPga), and dynamic lung compliance.
Study burden and risks
There is no study drug admission involved in this study and no study procedure
is experimental. Although some of these tests are very specialized, all are
performed as part of the clinical evaluation of some patients with respiratory
muscle function abnormalities due to neuromuscular disease such as Pompe
disease.
There is a risk the patiënt may feel bad from a study procedure. Some of these
risks are listed below but doctors and study sponsors cannot know all risks
that may occur. These vary from person to person.
Blood Pressure: A rubber cuff will squeeze one arm and may make you feel funny,
like your hand is asleep.
Nose Tubes: Swallowing the tubes may cause some discomfort. Local anesthetic is
used in the nose and back of the throat to reduce any discomfort. Although
unlikely, a sore throat, nose bleed, or sinusitis may result.
Breathing Tests: Blowing into the mouthpiece may make you feel dizzy or
light-headed so these tests are done with you seated in a chair. Inhaling
carbon dioxide temporarily will increase your breathing rate, which may be a
little alarming but does not last long. When the nerves are stimulated, you may
feel a strange sensation like a big hiccup and feel a strong twitch in your arm
and leg muscles but it is not dangerous.
Digital Drive 105
Novato CA 94949
US
Digital Drive 105
Novato CA 94949
US
Listed location countries
Age
Inclusion criteria
* Willing and able to provide written informed consent, after the nature of the study has been explained, and prior to any study-related procedures
* Documented diagnosis with late-onset Pompe disease based on GAA gene mutations and/or endogenous GAA activity <75% of the lower limit of the normal adult range reported by the testing laboratory, assessed by dried blood spot, whole-blood, skin fibroblasts, or muscle biopsy
* At least 18 years of age at study entry
* Willing and able to comply with all study procedures
Exclusion criteria
* Requires ventilatory support while awake and in the upright position. Subjects who require night time ventilator support may only enroll upon obtaining approval from the sponsor.
* Concurrent disease, medical condition, or extenuating circumstance that, in the opinion of the investigator, might compromise patient wellbeing,
study completion, or data collection.
- subjects with a diagnosis of asthma, chronic obstructive pulmonary disease, emphysema, or any other condition that may manifest with airway obstruction should be excluded, unless the subject has an FEV1/FVC ratio > 0.80 on spirometry (in another study or elsewhere) performed within 3 months in this study.
* Swallowing difficulty precluding balloon catheter placement (eg, esophageal strictures)
* Allergy to tools or procedures used for respiratory muscle testing
* Implanted ferrous metals (eg, cardiac pacemakers)
* Subjects taking medication for the treatment of obstructive lung disease (including, but not limited to, systemic or inhaled beta agonists, inhaled corticosteroids, or inhaled anticholinergic/anti-muscarinic agents) may not be enrolled in this study.
* Subjects who are pregnant, planning to become pregnant, or unable/unwilling to use effective contraception (as evaluated by the principal investigator) for the duration of the study.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL51709.091.15 |