A Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Duchenne Muscular Dystrophy

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02310763
• Date of registration: 04/11/2014
• Prospective Registration: Yes
• Primary sponsor: Pfizer
• Public title: A Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Duchenne Muscular Dystrophy
• Scientific title: A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTIPLE ASCENDING DOSE STUDY TO EVALUATE THE SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF PF-06252616 IN AMBULATORY BOYS WITH DUCHENNE MUSCULAR DYSTROPHY
• Date of first enrolment: November 24, 2014
• Target sample size: 121
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT02310763
• Study type: Interventional
• Study design: Allocation: Randomized. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Australia, Bulgaria, Canada, Italy, Japan, Poland, United Kingdom, United States

Contacts

• Name: Pfizer CT.gov Call Center
• Affiliation: Pfizer

Key inclusion & exclusion 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).



Age minimum: 6 Years
Age maximum: 15 Years
Gender: Male

Health Condition(s) or Problem(s) studied

Duchenne Muscular Dystrophy

Intervention(s)

Drug: Placebo

Biological: PF-06252616

Primary Outcome(s)

Change From Baseline on the 4 Stair Climb (4SC) as Compared to Placebo at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Liver Function [Time Frame: Baseline to Week 49 visit]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Renal Function [Time Frame: Baseline to Week 49 visit]

Number of Participants With Physical Examination Findings Reported as SAEs by Week 49 [Time Frame: Baseline to Week 49 visit]

Number of Participants With Vital Signs Findings Reported as SAEs by Week 49 [Time Frame: Baseline to Week 49 visit]

Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Week 49 [Time Frame: Study Day 1 to Week 49 visit]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Urinalysis [Time Frame: Baseline to Week 49 visit]

Height-adjusted Z-score of Lumbar Spine Bone Mineral Density Over Time by Week 49 [Time Frame: Screening and Week 49]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hematology [Time Frame: Baseline to Week 49 visit]

Number of Participants With Suicidal Ideation and Suicidal Behavior Reported as AEs by Week 49 [Time Frame: Baseline to Week 49 visit]

Bone Age to Chronological Age Ratio by Week 49 [Time Frame: Screening, Weeks 17, 33 and 49]

Categorical Summary of Liver Iron Accumulation by Week 49 [Time Frame: Screening, Weeks 13, 29 and 45]

Summary of Tanner Stage Rating by Week 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Compared to Placebo by Week 49 [Time Frame: Baseline to Week 49 visit]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hormones [Time Frame: Baseline to Week 49 visit]

Number of Participants Who Discontinued From the Study Due to TEAEs by Week 49 [Time Frame: Study Day 1 to Week 49 visit]

Number of Participants With Dose Reduced or Temporary Discontinuation Due to TEAEs by Week 49 [Time Frame: Study Day 1 to Week 49 visit]

Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria by Week 49 [Time Frame: Baseline to Week 49 visit]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Electrolytes [Time Frame: Baseline to Week 49 visit]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Clinical Chemistry [Time Frame: Baseline to Week 49 visit]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Fecal [Time Frame: Baseline to Week 49 visit]

Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Coagulation [Time Frame: Baseline to Week 49 visit]

Secondary Outcome(s)

Change From Baseline as Compared to Placebo on Forced Vital Capacity (FVC) at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Extension at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline as Compared to Placebo on PUL Overall Scores at Week 17 in Pre-specified Subsets [Time Frame: Baseline, Week 17]

Change From Baseline as Compared to Placebo on the Performance of Upper Limb (PUL) Overall Score at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline as Compared to Placebo on the Six Minute Walk Distance (6MWD) Score at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >=3.5 Seconds and <=8 Seconds) [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline to Week 97 on 6MWD for Participants in Sequence 1 Compared to the Natural History Control Group [Time Frame: Baseline, Week 97]

Change From Baseline to Week 97 on FVC for Participants in Sequence 1 Compared to the Natural History Control Group [Time Frame: Baseline, Week 97]

Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Flexion at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Terminal Half-life (t1/2) of Domagrozumab for Participants in Sequence 2 After the Last Dose of Domagrozumab [Time Frame: At predose, end of 2-hour infusion and 6 hours since start of infusion at Week 45]

Change From Baseline as Compared to Placebo on 6MWD at Week 49 in Pre-specified Subsets [Time Frame: Baseline, Week 49]

Change From Baseline as Compared to Placebo on FVC at Week 17 in Pre-specified Subsets [Time Frame: Baseline, Week 17]

Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC <3.5 Seconds) [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline as Compared to Placebo on 4SC at Week 49 in Pre-specified Subsets [Time Frame: Baseline, Week 49]

Change From Baseline as Compared to Placebo on NSAA at Week 33 in Pre-specified Subsets [Time Frame: Baseline, Week 33]

Change From Baseline to Week 97 on NSAA for Participants in Sequence 1 Compared to the Natural History Control Group [Time Frame: Baseline, Week 97]

Change From Baseline as Compared to Placebo on the Ankle Range of Motion (ROM) at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Trough (Pre-dose) Serum Concentration (Ctrough) of Domagrozumab [Time Frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3]

Change From Baseline as Compared to Placebo on the Northstar Ambulatory Assessment (NSAA) at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Number of Participants With Anti-drug Antibodies (ADA) Development by Week 97 [Time Frame: Baseline, every 4 weeks from Week 5 to Week 97 visit or early termination]

Trough Serum Concentration of GDF-8 (Ctrough,(GDF-8)) for Participants Receiving Domagrozumab in Period 1 [Time Frame: Every 4 weeks on dosing day (at predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 48]

Change From Baseline as Compared to Placebo on NSAA at Week 49 in Pre-specified Subsets [Time Frame: Baseline, Week 49]

Change From Baseline to Week 49 on 6MWD for Participants in Sequence 3 Compared to the Natural History Control Group [Time Frame: Baseline, Week 49]

Average Serum Concentration Over the Dosing Interval (Cav) of Domagrozumab [Time Frame: At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 1, 13, 17, 29, 33 and 45]

Change From Baseline as Compared to Placebo on 4SC at Week 17 in Pre-specified Subsets [Time Frame: Baseline, Week 17]

Change From Baseline as Compared to Placebo on 6MWD at Week 33 in Pre-specified Subsets [Time Frame: Baseline, Week 33]

Change From Baseline as Compared to Placebo on Muscle Strength of Hip Abduction at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline as Compared to Placebo on NSAA at Week 17 in Pre-specified Subsets [Time Frame: Baseline, Week 17]

Change From Baseline to Week 49 on 4SC for Participants in Sequence 3 Compared to the Natural History Control Group [Time Frame: Baseline, Week 49]

Change From Baseline as Compared to Placebo on PUL Overall Score at Week 49 in Pre-specified Subsets [Time Frame: Baseline, Week 49]

Ctrough,(GDF-8) for Participants of Sequence 3 in Period 2 [Time Frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 49 to Week 96]

Change From Baseline to Week 49 on NSAA for Participants in Sequence 3 Compared to the Natural History Control Group [Time Frame: Baseline, Week 49]

Time for Cmax (Tmax) of Domagrozumab [Time Frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3]

Change From Baseline to Week 97 on 4SC for Participants in Sequence 1 Compared to the Natural History Control Group [Time Frame: Baseline, Week 97]

Maximum Serum Concentration (Cmax) of Domagrozumab [Time Frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3]

Change From Baseline as Compared to Placebo on Muscle Strength of Knee Extension at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of Domagrozumab [Time Frame: At predose, end of 2-hour infusion,6 hours and 168 hours since start of infusion on Weeks 1, 13, 17, 29, 33 and 45]

Change From Baseline as Compared to Placebo on 4SC at Week 33 in Pre-specified Subsets [Time Frame: Baseline, Week 33]

Change From Baseline as Compared to Placebo on 6MWD at Week 17 in Pre-specified Subsets [Time Frame: Baseline, Week 17]

Change From Baseline as Compared to Placebo on FVC at Week 33 in Pre-specified Subsets [Time Frame: Baseline, Week 33]

Change From Baseline as Compared to Placebo on FVC at Week 49 in Pre-specified Subsets [Time Frame: Baseline, Week 49]

Change From Baseline as Compared to Placebo on Muscle Strength of Shoulder Abduction at Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Change From Baseline in Whole Thigh Muscle Volume Index Through Week 97 [Time Frame: Baseline, Weeks 17, 33, 49 and 97]

Change From Baseline as Compared to Placebo on PUL Overall Score at Week 33 in Pre-specified Subsets [Time Frame: Baseline, Week 33]

Change From Baseline in Whole Thigh Muscle Volume Through Week 97 [Time Frame: Baseline, Weeks 17, 33, 49 and 97]

Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >8 Seconds) [Time Frame: Baseline, Weeks 17, 33 and 49]

Concentration of Growth Differentiation Factor 8 (GDF-8) at Time 0 (Pre-dose),(C0(GDF-8) ) [Time Frame: Predose on Day 1 of Week 1]

Change From Baseline to Week 49 on FVC for Participants in Sequence 3 Compared to the Natural History Control Group [Time Frame: Baseline, Week 49]

Percent Change From Baseline as Compared to Placebo in Whole Thigh Muscle Volume Index by Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Clearance (CL) of Domagrozumab [Time Frame: At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 13, 29 and 45]

Percent Change From Baseline in Whole Thigh Muscle Volume as Compared to Placebo by Weeks 17, 33 and 49 [Time Frame: Baseline, Weeks 17, 33 and 49]

Volume of Distribution at Steady State (Vss) of Domagrozumab for Participants in Sequence 2 Required for Additional PK Assessment [Time Frame: At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Week 45]

Secondary ID(s)

B5161002

2014-002072-92

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 23/07/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02310763