A Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Duchenne Muscular Dystrophy
Condition: Duchenne Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Intervention: PF-06252616; Placebo
Intervention description: PF-06252616 IV Infusion, 3 dose levels (5mg/kg, 20 mg/kg and 40 mg/kg) will be investigated within each subject
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 121.0
Sex: Male
Minimum age: 6 Years
Maximum age: 15 Years
Healthy volunteers: No
Keywords: Duchenne Muscular Dystrophy, myostatin

Summary:

      This is a Phase 2 randomized, 2-period, double-blind, placebo-controlled, multiple ascending
      dose study to evaluate the safety, efficacy, PK and PD of PF-06252616 administered to
      ambulatory boys diagnosed with Duchenne Muscular Dystrophy. Three intravenous (IV) dose
      levels will be investigated in a within subject dose escalating fashion. Subjects will be
      randomly assigned to 1 of 3 sequence groups for approximately 96 weeks (2 periods of 48 weeks
      each). In period 1, two of the sequence groups will receive PF-06252616 and one sequence
      group will receive placebo. In period 2, the placebo group will switch to PF-06252616 and the
      two remaining sequence groups will either receive placebo or PF-06252616. Efficacy will be
      based on an observed mean change from baseline on function (4 stair climb) of PF-06252616 as
      compared to the placebo at the end of period 1. Period 2 provides an opportunity to evaluate
      PK. Subjects will receive monthly IV infused doses of either PF-06252616 or placebo and will
      undergo safety evaluations (Laboratory, cardiac monitoring, physical exams, x-ray, MRI),
      functional evaluations (pulmonary function testing, 4 stair climb, range of motion, strength
      testing, Northstar Ambulatory Assessment, upper limb functional testing and the six minute
      walk test), pharmacokinetic testing and pharmacodynamic testing to evaluate changes in muscle
      volume (MRI).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Ambulatory boys age 6 to <16 years old (at the time of randomization), diagnosed with
             DMD. Diagnosis must be confirmed in subject's medical history and by genetic testing
             obtained during routine clinical care for diagnostic purposes as reported from an
             appropriate regulated laboratory using a clinically validated genetic test (genetic
             testing is not provided by the sponsor).

          2. Subjects who are able to perform the 4 stair climb in > or = 0.33 but < or =1.6
             stairs/second.

          3. Subjects must be receiving glucocorticosteroids for a minimum of 6 months prior to
             signing informed consent. There should be no significant change (>0.2 mg/kg) in dosage
             or dose regimen (not related to body weight change) for at least 3 months immediately
             prior to signing the informed consent and a reasonable expectation that dosage and
             dosing regimen will not change significantly for the duration of the study.

          4. Adequate hepatic and renal function on screening laboratory assessments.

          5. No underlying disposition for iron accumulation on screening laboratory assessments.

          6. Iron content estimate on the screening liver MRI is within the normal range.

        Exclusion Criteria:

          1. Subjects with known cognitive impairment or behavioral issues that would impede the
             ability to follow instructions.

          2. History of major surgical procedure within 6 weeks of signing the informed consent or
             planned surgery during the study.

          3. Any injury which may impact functional testing. Previous injuries must be fully healed
             prior to consenting. Prior lower limb fractures must be fully healed and at least 3
             months from injury date.

          4. Presence or history of other musculoskeletal or neurologic disease or somatic disorder
             not related to DMD including pulmonary and cardiac disease.

          5. Compromised cardiac function (left ventricular ejection fraction <55% as determined on
             a screening cardiac MRI or echocardiogram). Subjects may be receiving ACE (angiotensin
             converting enzyme) inhibitors or beta blockers, ARB (angiotensin II receptor
             antagonist) or aldosterone blocker/thiazide diuretic; however they must have initiated
             treatment more than 3 months prior to screening to ensure stable therapy.

          6. Evidence or history of clinically significant hematological, renal, endocrine,
             pulmonary, gastrointestinal, cardiovascular (including uncontrolled hypertension),
             hepatic, neurologic, or allergic disease (including drug allergies, but excluding
             untreated, asymptomatic, seasonal allergies at time of dosing).

          7. Documented history of iron overload including hemochromatosis, beta thalassemia major,
             beta thalassemia intermedia or hemolytic anemia.

          8. Unwilling or unable (eg, metal implants, requires sedation) to undergo examination
             with closed MRI without sedation.

          9. Participation in other studies involving investigational drug(s) for a minimum of 30
             days or within 5 half lives (whichever is longer) prior to signing the informed
             consent and/or during study participation.

         10. Current or prior treatment with anti-myostatin, exon skipping, nonsense mutation
             targeted therapies ever or more than 30 days of treatment with utrophin modifiers and
             treatment with utrophin modifiers within 30 days prior ot signing the informed consent
             and/or during study participation.

         11. Current or prior treatment within the past 3 months with androgens or human growth
             hormone.

         12. Current treatment with immunosuppressant therapies (other than glucocorticoid
             steroids), aminoglycosides (eg, gentamicin), multi vitamins with iron and iron
             supplements and other investigational therapies (including idebenone).