Phase 3 Trial of Pamrevlumab or Placebo in Combination With Systemic Corticosteroids in Participants With Ambulatory DMD



Sponsor:   FibroGen


Sommario: To evaluate the efficacy and safety of pamrevlumab versus placebo in combination with
systemic corticosteroids administered every 2 weeks in ambulatory participants with
Duchenne muscular dystrophy (DMD) (age 6 to <12 years).




TIPOLOGIA STUDIO

 
Interventistico



FASE

 
Fase 3




TRATTAMENTO

  
    
  
  • Pamrevlumab
  • Placebo
  • Corticosteroids
    • 






OBIETTIVO PRIMARIO


  
  • Misura: Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52
  • Tempo: Baseline, Week 52
  • Descrizione: The NSAA consisted of 17 activities, each scored as 0 (activity could not be performed),
1 (modified method but achieved goal without physical assistance from another), or 2
(normal, achieved goal without assistance). The sum of these 17 scores was used to form a
total score ranging from 0 (worst) to 34 (fully independent function). If fewer than 15
of the 17 activities were performed, the total score was considered missing. If 15 to 16
activities were performed, the total score was calculated by multiplying the sum of the
scores in the x activities that were performed by 17/x. If an activity could not be
performed due to disease progression/loss of ambulation, a score of 0 was assigned.
Higher scores indicated better functioning. Least square (LS) mean and standard error
(SE) were analyzed using a mixed model for repeated measure (MMRM).




OBIETTIVO SECONDARIO


  
  • Misura: Change From Baseline in 4-Stair Climb Velocity (4SCV) Assessment at Week 52
  • Tempo: Baseline, Week 52
  • Descrizione: The 4SCV (centimeters [cm]/second [sec]) was calculated as the ratio of the total height
(cm) of stairs climbed divided by the number of seconds taken to complete the 4-stair
climb.
  • Misura: Change From Baseline in the 10-Meter Walk/Run Test at Week 52
  • Tempo: Baseline, Week 52
  • Descrizione: The time (in sec) required for a participant to run or walk a distance of 10 meters as
quickly as possible was calculated as velocity (meters/sec).
  • Misura: Change From Baseline in Time to Stand (TTSTAND) at Week 52
  • Tempo: Baseline, Week 52
  • Descrizione: The time (in sec) required for a participant to stand from supine position has been
reported. A longer time taken reflected a worse outcome.
  • Misura: Time to Loss of Ambulation (LoA) From Baseline to Week 52
  • Tempo: Baseline to Week 52
  • Descrizione: Time (days) to LoA was defined as the number of days from randomization to the date of
LoA, or all-cause death based on observed data, whichever occurred earlier during the
on-study period. Median time (days) to LoA was calculated using Kaplan Meier Survival
Estimates.




CRITERI DI ELIGIBILITA'


    
             
  • 
        Criteri di inclusione e esclusione
        
    Inclusion Criteria:

Age, and consent:

  1. Males at least 6 to <12 years of age at screening initiation

  2. Written consent by participant and/or legal guardian as per regional/ country and/or
     Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements

     DMD diagnosis:

  3. Medical history includes diagnosis of DMD and confirmed Duchenne mutation, including
     status of exon 44 using a validated genetic test.

     Pulmonary criteria:

  4. Average (of screening and Day 0) percent predicted forced vital capacity (FVC) above
     45%

  5. On a stable dose of systemic corticosteroids for a minimum of 6 months, with no
     substantial change in dosage for a minimum of 3 months (except for adjustments for
     changes in body weight) prior to screening. Corticosteroid dosage should be in
     compliance with the DMD Care Considerations Working Group recommendations (for
     example, prednisone or prednisolone 0.75 mg/kg per day or deflazacort 0.9 mg/kg per
     day) or stable dose. A reasonable expectation is that dosage and dosing regimen
     would not change significantly for the duration of the study.

     Performance criteria:

  6. Able to complete 6-minute walking distance (6MWD) test with a distance of at least
     270 meters but no more than 450 meters on two occasions within 3 months prior to
     randomization with ≤10% variation between these two tests.

  7. Able to rise (TTSTAND) from floor in <10 seconds (without aids/orthoses) at
     screening visit.

  8. Able to undergo magnetic resonance imaging (MRI) test for the lower extremities
     vastus lateralis muscle.

     Vaccination:

  9. Agreement to receive annual influenza vaccinations during the conduct of the study.

     Laboratory criteria:

 10. Adequate renal function: cystatin C ≤1.4 mg/liter (L)

 11. Adequate hematology and electrolytes parameters:

       1. Platelets >100,000/microliter (μL)

       2. Hemoglobin >12 grams (g)/deciliter (dL)

       3. Absolute neutrophil count >1500/μL

       4. Serum calcium (Ca), potassium (K), sodium (Na), magnesium (Mg) and phosphorus
          (P) levels are within a clinically accepted range for DMD participants

 12. Adequate hepatic function:

       1. No history or evidence of liver disease

       2. Gamma glutamyl transferase (GGT) ≤3x upper limit of normal (ULN)

       3. Total bilirubin ≤1.5xULN

Exclusion Criteria:

General Criteria:

  1. Concurrent illness other than DMD that can cause muscle weakness and/or impairment
     of motor function

  2. Severe intellectual impairment (for example, severe autism, severe cognitive
     impairment, severe behavioral disturbances) preventing the ability to perform study
     assessments in the Investigator's judgment

  3. Previous exposure to pamrevlumab

  4. Body mass index (BMI) ≥40 kg/square meter (m^2) or weight >117 kg

  5. History of

       1. allergic or anaphylactic reaction to human, humanized, chimeric or murine
          monoclonal antibodies

       2. hypersensitivity to study drug or any component of study drug

  6. Exposure to any investigational drug (for DMD or not), in the 30 days prior to
     screening initiation or use of approved DMD therapies (for example, eteplirsen,
     ataluren, golodirsen, casimersen) within 5 half-lives of screening, whichever is
     longer with the exception of the systemic corticosteroids, including deflazacort

     Pulmonary and Cardiac criteria:

  7. Requires ≥16 hours continuous ventilation

  8. Poorly controlled asthma or underlying lung disease such as bronchitis,
     bronchiectasis, emphysema, recurrent pneumonia that in the opinion of the
     investigator might impact respiratory function

  9. Hospitalization due to respiratory failure within the 8 weeks prior to screening

 10. Severe uncontrolled heart failure (New York Heart Association [NYHA] Classes III-IV)
     or renal dysfunction, including any of the following:

       1. Need for intravenous diuretics or inotropic support within 8 weeks prior to
          screening

       2. Hospitalization for a heart failure exacerbation or arrhythmia within 8 weeks
          prior to screening

       3. Participants with glomerular filtration rate (GFR) of less than 30 mL/minute
          (min)/1.73 m^2 or with other evidence of acute kidney injury as determined by
          investigator

 11. Arrhythmia requiring anti-arrhythmic therapy

 12. Any other evidence of clinically significant structural or functional heart
     abnormality

     Clinical judgment:

 13. The Investigator judges that the participant will be unable to fully participate in
     the study and complete it for any reason, including inability to comply with study
     procedures and treatment, or any other relevant medical, surgical or psychiatric
     conditions
    
        
    • 
    




SESSO

  
Maschi




  


ETA' MINIMA



Età Minima: 6 Years

Età Massima: 11 Years






LUOGO


  
IRRCS Ospedale San Raffaele
Milano, 20132
Istituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea - Lombardia
Bosisio ParIni, 23842
Centro Clinico NeMO
Milano, 20162
Fondazione Policlinico Universitario Agostino Gemelli
Roma, 168
Ospedale Pediatrico Bambino Gesù - Roma - Gianicolo
Roma,