Primary:* To assess the efficacy of idebenone compared to placebo, in delaying the loss of respiratory function in patients with DMD receiving glucocorticoid steroids as measured by changes in Forced Vital Capacity percent predicted (FVC %p) using…
ID
Source
Brief title
Condition
- Muscle disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the efficacy of idebenone compared to placebo, in delaying the loss
of respiratory function in patients with DMD receiving glucocorticoid steroids
as measured by changes in Forced Vital Capacity percent predicted (FVC %p)
using clinic-based spirometry.
Secondary outcome
Secondary: To assess the efficacy of idebenone compared to placebo in delaying
the loss of respiratory function in patients with DMD receiving glucocorticoid
steroids as measured by:
- Changes in Peak Expiratory Flow percent predicted (PEF %p) using clinic-based
spirometry
- Time to loss of 10% of Baseline Forced Vital Capacity (FVC) using
clinic-based spirometry
* To assess the efficacy of idebenone compared to placebo in delaying the loss
of inspiratory muscle function as measured by changes in Inspiratory Flow
Reserve (IFR) using clinic-based spirometry.
Other:
* To assess the safety and tolerability of idebenone in patients with DMD
receiving glucocorticoid steroids
Background summary
Duchenne Muscular Dystrophy is a condition that affects about 1 in every 3*000
boys. The disease affects the muscles, including muscles involved in breathing
and the heart. There is a need to develop new treatments for this disease and
also to assess the safety, tolerability and efficacy of these treatments.
Idebenone is a small molecule optimized to facilitate the transport of
electrons within mitochondria ("cellular power plants"), and contributes to
maintaining correct electron flow, which is necessary for the production of
cellular energy. Nerve and muscle cells, including lung and heart muscle cells,
are particularly energy-demanding and are, therefore, more prone to rapid loss
of function or death due to the mitochondria not producing energy properly.
Through preserving mitochondrial function and protecting cells from oxidative
damage, it is believed that idebenone can prevent cell damage and increase the
production of energy within impaired nerve and muscle tissue in DMD patients.
Study objective
Primary:
* To assess the efficacy of idebenone compared to placebo, in delaying the loss
of respiratory function in patients with DMD receiving glucocorticoid steroids
as measured by changes in Forced Vital Capacity percent predicted (FVC %p)
using clinic-based spirometry.
Secondary:
* To assess the efficacy of idebenone compared to placebo in delaying the loss
of respiratory function in patients with DMD receiving glucocorticoid steroids
as measured by:
- Changes in Peak Expiratory Flow percent predicted (PEF %p) using clinic-based
spirometry
- Time to loss of 10% of Baseline Forced Vital Capacity (FVC) using
clinic-based spirometry
-To assess the time to clinically relevant events and disease
milestones.
* To assess the efficacy of idebenone compared to placebo in delaying the loss
of inspiratory muscle function as measured by changes in Inspiratory Flow
Reserve (IFR) using clinic-based spirometry.
Other:
* To assess the safety and tolerability of idebenone in patients with DMD
receiving glucocorticoid steroids
Study design
The study will be a double-blind, randomized, placebo-controlled,
parallel-group, multicenter study evaluating idebenone versus placebo.
Due to the very high power of the study (based on a protocol-specified
re-evaluation of the data variability and study power conducted in April 2020)
and the unmet medical need in this patient population, an interim analysis will
be conducted in Q3/Q4 2020. The interim analysis will test if the study can be
terminated early due to compelling efficacy or terminated early due to futility.
In the event the study is terminated early due to compelling efficacy, all
patients will be asked to continue treatment and attend Visit 8/End of
treatment at site (to be scheduled within 1 month after decision to terminate
the study) for safety assessments only. At Visit 8 all patients will be offered
the possibility to roll over into the SIDEROS-Extension (SIDEROS-E) study. For
those patients participating in SIDEROS-E, Visit 8 will also be the End of
study visit. For those patients not participating in SIDEROS-E, Visit
9/Follow-up (for safety follow-up) will be the End of study visit, which will
take place 4 weeks after Visit 8/End of treatment.
In the event the study is terminated early due to futility based on the interim
analysis, all patients will be asked to stop treatment immediately and attend
Visit 9/Follow-up End of study visit, 4 weeks after treatment is stopped.
Intervention
The patients are randomized in a 1:1 ratio to blinded administration of oral
idebenone or placebo in order to reach a minimum of 200 evaluable
glucocorticoid steroids using patients.
Group A: 900 mg idebenone/day
Group B: Matching placebo tablets
Two tablets are to be taken orally three times a day with meals.
Study burden and risks
Risks:
Capnography:
A machine called a capnograph will provide a picture of the carbon dioxide
(CO2) that you exhale, in the form of carbon dioxide (CO2) waves that will
provide valuable information to your doctor about your respiratory system. A
very small, soft tube will be attached to your nose (both nostrils) for a few
minutes to capture the exhaled air and sends it to the machine that measures
the carbon dioxide. This is a short, safe procedure that shouldn*t cause you
any discomfort.
Breathing tests:
For the breathing test, you will need to breathe into a special machine. You
will be shown how to do it but here is a description of what to do: First you
will need to take a deep breath in and make sure that your lips are sealed
around the mouthpiece. You will then need to blow out into the machine as fast
as you can until your lungs are empty. How long it will take you to do this
test depends on how big your lungs are but it usually takes a few seconds. You
might also be asked to breathe in again and breathe out slowly for as long as
you can.
You might need to have a clip put on your nose so that you are not breathing
out through your nose at the same time or you might need a small mask on your
face if you cannot fully seal your lips on the mouthpiece.
You will be given a small machine called the nmd-1 device to take home with you
to use between visits. This is to measure the same things as the hospital tests
measure, but at home. The respiratory therapist will show you how to use this
machine. You should not feel unwell when you are doing these tests at hospital
and at home but you might feel a little bit dizzy or breathless because you
have been breathing so deeply.
You will be allowed to make the 5-min breaks for a rest between the
examinations.
The breathing tests including the home examinations with the nmd-1 device are
harmless and will simply measure how well and how forcefully you can breathe in
and out.
Blood oxygen saturation (O2 Sat)
The *Blood oxygen saturation* test will be done during hospital visits to
measure the quantity of oxygen in your blood using a device that is placed on
your finger for a short period of time (1-2 minutes) and shouldn*t cause you
any discomfort.
Electrocardiogram (ECG)
There is one test for measuring the heart, an electrocardiogram (ECG). This
test is also non-invasive and not painful. The electrocardiogram (ECG) is a
tracing of your heart beating, made by recording tiny changes of electricity
produced by your heart at the surface of the skin. To record these changes
electrode stickers will be put on your chest with wires attached to them. It
will take about 5-10 minutes.
Blood sample analysis
Blood samples will be collected for examination at each visit. Collecting the
blood samples will be the only procedure that might cause discomfort during the
study. There will be approximately 10 ml collected at each study visit, the
equivalent of about 2 teaspoons. During the entire study, approximately 100 ml
of your blood will be collected. Your blood samples will be sent out of the
hospital on the same day they have been collected to a central laboratory,
based in the United Kingdom, for analysis. Your blood samples will be fully
used to perform the analyses and will not be retained neither at the hospital
neither at the central laboratory.
Benefits:
It is not yet fully known how idebenone will help your illness, but through
data collected until now in previous studies, it is believed that idebenone
will slow the decline of your respiratory function. Also, other people with a
similar condition may benefit from the knowledge obtained from this research
study. However it is not guaranteed that your participation in the study will
bring you any benefit.
Hohenrainstrasse 24
Pratteln CH-4410
CH
Hohenrainstrasse 24
Pratteln CH-4410
CH
Listed location countries
Age
Inclusion criteria
1. Male patients with a 35% * FVC * 80% of predicted value at
Screening and at Baseline and who, in the opinion of the investigator are
in the respiratory function decline phase.
2. Minimum 10 years old at Screening.
3. Signed and dated Informed Consent Form.
4. Documented diagnosis of DMD (severe dystrophinopathy) and clinical features
consistent of typical DMD at diagnosis (i.e.
documented delayed motor skills and muscle weakness by
age 5 years). DMD should be confirmed by mutation analysis
in the dystrophin gene or by substantially reduced levels of dystrophin protein
(i.e. absent or <5% of normal) on Western blot or immunostaining.
5. Chronic use of systemic glucocorticoid steroids for DMD related conditions
continuously for at least 12 months prior to Baseline without any dose
adjustments on a mg/kg basis in
the last 6 months (only dose adjustment determined by weight changes are
allowed).
6. Ability to provide reliable FVC values at Screening and Baseline, and
reproducible within 15% (relative change) at Baseline compared to
Screening.
7. Patients assessed by the Investigator as willing and able to comply with the
requirements of the study, possess the required cognitive abilities and are
able to swallow study
medication.
8. Patients who prior to screening have been immunized with 23-valent
pneumococcal polysaccharide vaccine or any other pneumococcal polysaccharide
vaccine as per national recommendations, as well as annually immunized with
inactivated influenza vaccine.
Exclusion criteria
1. Symptomatic heart failure (defined as patients with structural heart
disease, dyspnea, fatigue and impaired tolerance to exercise; Stage C by the
ACCF/AHA guideline or NYHA Classes III-IV) and/or symptomatic ventricular
arrhythmias.
2. Ongoing participation in any other therapeutic trial and/or intake of any
investigational drug within 90 days prior to Baseline (only exception allowed
is use of Deflazacort in US
as part of the Expanded Access Program or any approved corticosteroid product
in trial for regimen optimization , for which the patient met the inclusion
criterion 5)
3. Ongoing exon-skipping or read-through gene therapy for DMD; previous
exon-skipping or read-through gene therapy is allowed if the stop date was more
than 6 months prior to
Screening.
4. Planned or expected spinal fixation surgery during the study period (as
judged by the Investigator, i.e. due to rapidly progressing scoliosis), prior
spinal fixation surgery is allowed if
it took place more than 6 months prior to Screening.
5. Asthma, bronchitis/COPD, bronchiectasis, emphysema, pneumonia or presence of
any other non-DMD respiratory illness that affects respiratory function.
6. Chronic use of beta2-agonists or any use of other
bronchodilating/bronchoconstricting medication (inhaled
steroids, sympathomimetics, anti-cholinergics, antihistamines); chronic use is
defined as a daily intake for more than 14 days.
7. Any bronchopulmonary illness that required treatment with antibiotics within
3 months prior to Screening.
8. Moderate or severe hepatic impairment as assessed and documented by the
investigator ( Liver function tests LFT, medical history or when the parameters
of the formula are available to site ( (see Appendix B),child-Pugh class B [7
to 9 points] or Child-Pugh class C [10 to 15 points] could be indicative of
such conditions) or severe renal impairment (eGFR <30 mL/min/1.73 m2).
9. Prior or ongoing medical condition or laboratory abnormality which in the
Investigator*s opinion may put the patient at significant risk, may confound
the study results or may
interfere significantly with the patient*s participation in the
study1.
10. History of or current drug or alcohol abuse or use of any tobacco/marijuana
products/smoking.
11. Known individual hypersensitivity to idebenone or to any of the
ingredients/excipients of the study medication.
12. Daytime ventilator assistance (defined as use of any assisted ventilation
while awake).
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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metc-ldd@lumc.nl
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metc-ldd@lumc.nl
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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 |
|---|---|
| EudraCT | EUCTR2016-000602-10-NL |
| CCMO | NL58933.058.16 |