The primary objective is to test the hypothesis that once daily tadalafil administered orally for 48 weeks lessens the decline in ambulatory ability as measured by the 6MWD compared to placebo in boys with Duchenne muscular dystrophy (DMD). Two…
ID
Source
Brief title
Condition
- Muscle disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy measure is:
- 6-minute walk distance (6MWD)
Secondary outcome
Secondary efficacy measures are:
- North Star Ambulation Assessment (NSAA)
- Timed function tests (rise from floor from supine, 10 meter walk/run, 4-stair
climb/descend)
Background summary
Duchenne muscular dystrophy (DMD) is a fatal, muscle-wasting disease typically
diagnosed in young boys, for which there are no approved disease-specific
treatments. Gene therapy and stem cell transplants have yielded limited
clinical progress. While approaches to restore dystrophin expression in muscle
by overcoming specific mutations (for example, exon-skipping or stop codon
read-through strategies) have been more encouraging, these approaches are
limited in their applicability to a relatively small percentage of boys with
DMD with these specific mutations. A pharmacological approach to treat the
broader population of boys with DMD irrespective of genetic mutation by
targeting a pathophysiological mechanism downstream from dystrophin deficiency
would address a substantial unmet medical need.
Non-clinical and early clinical studies have provided proof-of-concept that
PDE5 inhibition with tadalafil may have favorable effects to preserve muscle
function in DMD by improving exercise-induced blood flow to muscle,
ameliorating a key dysfunction in this disease. Study H6D-MC-LVJJ (LVJJ), is a
Phase 3, global, multicenter, randomized, double-blind, placebo-controlled,
parallel, 3-arm study to determine the efficacy and safety of tadalafil
administered orally once daily in ambulatory boys with DMD who are already
receiving treatment with corticosteroids.
Study objective
The primary objective is to test the hypothesis that once daily tadalafil
administered orally for 48 weeks lessens the decline in ambulatory ability as
measured by the 6MWD compared to placebo in boys with Duchenne muscular
dystrophy (DMD). Two doses of tadalafil (0.3 mg/kg and 0.6 mg/kg) will be
compared to placebo.
The secondary objectives of the study are to:
• test the hypothesis that once daily tadalafil administered orally for 48
weeks compared with placebo in boys with DMD:
- lessens the decline in North Star Ambulatory Assessment (NSAA) global score,
- lessens the decline in performance on timed function tests: rise from floor
from supine, 10 meter walk/run, stair climb and stair descend,
- delays the time to persistent 10% worsening in the 6MWD,
- delays the time to persistent 10% worsening in timed function tests: rise
from floor from supine, 10 meter walk/run test, stair climb, and stair descend,
- lessens the decline in Quality of Life (QoL), as measured by the Pediatric
Outcomes Data Collection Instrument (PODCI) global functioning scale and the
following core scales: Upper Extremity/Physical Functioning, Transfer/Basic
Mobility and Sports/Physical Functioning (Daltroy et al. 1998).
• characterize the PK of tadalafil in pediatric DMD patients, and assess
relationships between tadalafil exposure and efficacy and safety outcomes.
The exploratory objectives related to ambulatory endpoints of the study are to
assess the effect that once daily tadalafil administered orally for 48 weeks
compared with placebo in boys with DMD:
• lessens the decline in ambulatory ability as measured by:
- Percent change from baseline in the 6MWD, and
- Change from baseline in the percent of predicted 6MWD based on patient age
and height
• lessens the decline in ambulatory ability as measured by individual
components of the NSAA
The other exploratory objectives of the study are to assess the effect that
once daily tadalafil administered orally for 48 weeks compared with placebo in
boys with DMD:
- lessens the decline in upper limb performance as measured by the Performance
of the Upper Limb (PUL) Scale
- lessens the decline in pulmonary function as measured by spirometry
- reduces resting heart rate as measured by ECG.
Study design
Phase 3, global, multicenter, randomized, double-blind, placebo-controlled,
parallel, 3-arm study of tadalafil in patients with DMD. The study will consist
of a 48-week double-blind treatment phase, followed by a 48-week open label
extension phase. The two daily tadalafil target doses to be tested are 0.3
mg/kg and 0.6 mg/kg.
Intervention
During the double-blind period, tadalafil or matching placebo will be
administered orally once daily at one of 2 target doses (0.3 mg/kg or 0.6
mg/kg). A dosing algorithm will be used to achieve each of the 2 daily target
doses in different weight categories using a combination of existing tadalafil
(Cialis) tablet strengths (2.5-, 5-, 10-, and 20-mg) or matching placebo
tablets.
During the open-label extension period all patients will initially receive
tadalafil, but still blinded to the target dose, either 0.3 mg/kg or 0.6 mg/kg.
Patients assigned to tadalafil during the double-blind treatment period will
begin the extension period on the same target dose of tadalafil. Patients
assigned to placebo during the double-blind treatment phase will be randomized
to receive either tadalafil 0.3 mg/kg or 0.6 mg/kg during the OLE. The final
target dose studied in the extension period will be dependent on the final
unblinded results from the primary 48-week efficacy analysis at the completion
of the double-blind treatment period.
Study burden and risks
There are risks involved with the use of the investigator product tadalafil and
the study procedures. An overview is provided in appendix 3 of the informed
consent document for parents / legal guardians. There may also be other unknown
risks involved with the medication and study procedures and their combination.
Although the study drug is being tested as a possible treatment for DMD, the
subject may not receive any medical benefit. The results of the tests may
provide the patient information on his health and information obtained from
this study may benefit patients in the future.
Lilly Corporate Center NA
Indianapolis IN 46285
US
Lilly Corporate Center NA
Indianapolis IN 46285
US
Listed location countries
Age
Inclusion criteria
• Males with proven DMD ;• Ages 7-14 years inclusive;• Ambulant, defined as baseline 6MWD between 200 and 400 meters inclusive ;• Baseline 6MWD measurements within 20% of the screening 6MWD;• Left ventricular ejection fraction (LVEF) >=50% ;• Receiving systemic corticosteroids for a minimum of 6 months immediately prior to screening, with no significant change in total daily dosage or dosing regimen (except those adjusting for weight changes) for a minimum of 3 months immediately prior to screening and a reasonable expectation that total daily dosage and dosing regimen will not change significantly (except for adjustments for weight) for the duration of the study.
Exclusion criteria
• Symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) ;• Change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiating) in prophylactic treatment for heart failure within 3 months prior to start of study treatment;• Cardiac rhythm disorder defined as sinus rhythm with ectopic contractions or conductance disturbances, or any rhythm other than sinus, observed on screening ECG ;• Use of continuous mechanical ventilator assistance. [Evening use of bi-level positive airway pressure (BPAP) or continuous positive airway pressure (CPAP) therapy is allowed];• Previous treatment with investigational drugs or interventions (including shock training system) within 3 months of the first administration of study medication, or planned use during the study ;• History of participation in gene or cell-based therapy ;• History of antisense oligonucleotide (AON) or stop codon read-through therapy ;• Unable to take orally administered tablets (without chewing, crushing or breaking), as assessed by the investigator ;• Use of L-arginine supplements within 4 weeks (+/- 1 day) of the first administration of study medication ;• Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength within 3 months prior to the start of study treatment (e.g., growth hormone, anabolic steroids including testosterone). Vitamin D, calcium, and combinations thereof will be allowed.;• New or changed treatment with herbal or dietary supplements being taken with an expectation of an effect on muscle strength or function during 1 month prior to first dose of study drug. Patients taking herbal or dietary supplements as defined above with no change in type or dose for 1 month prior to first dose of study drug with no expectation of adding or changing supplements for the 48 week double-blind period may be enrolled. ;• Surgery that might have an effect on muscle strength or function within 3 months before study entry or planned surgery at any time during the study;• Evidence of a lower limb injury that may in the judgment of the investigator affect performance on the 6MWD;• Severe behavioral problems, including severe autism or attention deficit disorders, that may in the judgment of the investigator interfere with completion of the 6MWD ;• Any contraindication to tadalafil (use of any form of organic nitrate, either regularly and/or intermittently, or known serious hypersensitivity to tadalafil);• History of significant renal insufficiency, defined as receiving renal dialysis or having a screening serum cystatin C level >= 2.35 mg/L ;• Clinical evidence of cirrhosis ;• Diagnosed with a retinal disorder (for example, hereditary retinal disorders, retinopathy of prematurity);• Have severe hypotension or uncontrolled hypertension as determined by the investigator;• Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy (protease inhibitor), systemic ketoconazole, or systemic itraconazole, or chronic use of potent CYP3A4 inducers, such as rifampicin;• Currently receiving treatment with doxazosin, nitrates, or cancer therapy;• Have known allergy to any of the excipients in tadalafil tablets, notably lactose;• Current PDE5 inhibitor therapy or treatment within the past 6 months ;• Other medical condition deemed to place the patient at potential increased risk or reduced adherence to the study protocol ;• History of loss of vision in 1 eye because of nonarteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous phosphodiesterase type 5 (PDE5) inhibitor exposure.
Design
Recruitment
Medical products/devices used
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 | EUCTR2013-001194-25-NL |
| ClinicalTrials.gov | NCT01865084 |
| CCMO | NL45034.058.13 |