| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Duchenne Muscular Dystrophy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Fatal muscle wasting disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10013801 |
| E.1.2 | Term | Duchenne muscular dystrophy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
Test the hypothesis that once daily tadalafil administered orally for 48 weeks compared with placebo in boys with DMD:
o lessens the decline in North Star Ambulatory Assessment (NSAA) global score,
o lessens the decline in performance on timed function tests: rise from floor from supine, 10 meter walk/run, stair climb and stair descend,
o delays the time to persistent 10% worsening in the 6MWD,
o 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,
o 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.
o Characterize the PK of tadalafil in pediatric DMD patients, and assess relationships between tadalafil exposure and efficacy and safety outcomes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Males with proven DMD
• Ages 7-14 years inclusive
• Ambulant, defined as baseline 6MWD between 200 and 400 meters inclusive at screening and baseline
• Baseline 6MWD measurements within 20% of the screening 6MWD.
• Left ventricular ejection fraction (LVEF) ≥50%
• Receiving systematic 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. |
|
| E.4 | Principal 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy measure is the 6MWD, and the primary endpoint will be the comparison of the change in the 6MWD after 48 weeks in tadalafil and placebo patients. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening, Week 0, Week 12, Week 24, Week 36, Week 48, Week 60, Week 96 and Week 144. |
|
| E.5.2 | Secondary end point(s) |
The North Star Ambulatory Assessment (NSAA)
Timed function tests (rise from floor from supine, 10 meter walk/run, 4-stair climb/descend)
Decline in Quality of Life (QoL), as measured by the Pediatric Outcomes Data Collection Instrument (PODCI) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
NSAA and 6MWD:
Screening, Week 0, Week 12, Week 24, Week 36, Week 48, Week 60, Week 96, (Week 144 only for 6MWD).
PODCI:
Week 0, Week 12, Week 24, Week 48,Week 96
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Netherlands |
| Russian Federation |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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