| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Duchenne's Muscular Dystrophy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Duchenne's Muscular Dystrophy |
|
| 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 | 20.0 |
| 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 |
- To determine the safety and tolerability of multiple ascending repeat IV doses of PF-06252616 in ambulatory boys with DMD.
- To demonstrate the efficacy of treatment with IV doses of PF-06252616 based on an observed mean change from baseline on function (4 Stair Climb) as compared to placebo following 49 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the effects of PF-06252616 on muscle strength and other functional assessments compared to placebo
- To evaluate the PD activity of PF-06252616 based on the percent change of muscle volume from baseline as compared to placebo
- To evaluate the PD profile of PF-06252616 based on GDF-8 (myostatin) modulation in serum
- To characterize the PK profile of PF-06252616
- To evaluate the immunogenicity of PF-06252616
- To characterize the long-term effects following approximately 2-years of treatment with PF-06252616 on functional assessments compared to historical control.
- To characterize the effects of PF-06252616 on muscle strength and functional assessments compared to placebo in subset of subjects who may demonstrate a rapid disease decline and with relatively low variability over a one-year period. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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). Results must confirm the presence of a mutation in the dystrophin gene(s) which is clinically consistent with the diagnosis of DMD.
2. Subjects who are able to perform the 4 stair climb in ≥0.33 but ≤1.6 stairs/second at screening.*
3. Evidence of a personally signed and dated informed consent and assent (where appropriate) document indicating that the subject and a legally acceptable representative/parent(s)/legal guardian have been informed of all pertinent aspects of the study.
4. Subjects and their legal guardians who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Subjects will be required to provide assent in compliance with local regulations and IRB requirements.
5. 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.
6. Adequate hepatic and renal function on screening laboratory assessments:
•GGT ≤upper limit of normal (ULN).
•Alkaline phosphatase ≤ULN.
•Total Bilirubin ≤ULN.
•Serum Albumin≥LLN.
•Serum creatinine ≤ULN.
7. No underlying disposition for iron accumulation on screening laboratory assessments:
•Serum Iron≤1.2 x ULN.
•Serum Ferritin ≤140 ng/mL.
•% Transferrin Saturation ≤50%.
8. No underlying disposition for bleeding disorder on screening laboratory assessments:
•PT/INR ≤1.25 x ULN.
•aPTT ≤1.25x ULN.
•Fecal occult blood is negative. If the fecal occult blood is positive due to known pre-exiting medical condition (eg. any cause of rectal bleeding; hemorrhoids, anal fissure) that is not considered to be clinically significant by the investigator, the subject may be included.
9. Iron content estimate on the screening liver MRI is within the normal range as determined by R2* value (R2*≤75 Hz at 1.5 T or R2*≤139 Hz at 3.0 T).
*Note: The 4 stair climb is expressed as a velocity in the inclusion criteria rather than a time in seconds in an attempt to reduce the risk of subjects purposefully manipulating their performance at screening in order to enroll. To determine eligibility subjects must have a 4 SC that is ≥2.5s but ≤12s on the screening assessment. It is not necessary to calculate the velocity. |
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| E.4 | Principal 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, beta blockers, ARB (angiotensin II receptor blocker) 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 to 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).
13. History of allergic or anaphylactic reaction to a therapeutic or diagnostic protein or additives of this investigational product (histidine, sucrose, edetic acid [ethylenediaminetetraacetic acid], and polysorbate 80).
14. Have suicidal ideation and behavior associated with actual intent and/or method and/or plan and/or action (eg, self-harming behaviors) in the past 6 months based on the Columbia-Suicide Severity Rating Scale (C-SSRS Children’s Baseline/Screening Appendix 1) or at baseline (C-SSRS Children’s Since Last Visit Appendix 2).
15. Subjects who, in the opinion of the investigator, are biologically capable of having children and are sexually active who are unwilling or unable to use a condom to prevent potential transfer of exposure to drug through semen; male subjects of childbearing potential, with their female partners at risk for pregnancy, who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol (in addition to the condom to prevent potential transfer of drug through semen) for the duration of the study and through completion on final study visit.
16. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are related to Pfizer employees directly involved in the conduct of the study.
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
Note: Screening laboratory tests with results considered by the investigator to be transient and inconsistent with the subject’s clinical condition may be repeated once during the screening period for confirmation of eligibility. The reason for repeating the assessment should be documented. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
- Incidence of dose limiting or intolerability treatment related AEs by Week 49.
- Incidence, severity and causal relationship of treatment emergent AEs (TEAEs) and withdrawals due to TEAEs by Week 49.
- Incidence and magnitude of abnormal laboratory findings (clinical laboratory tests [hematology, chemistry, GGT, PT, aPTT, creatine kinase, amylase, serum ferritin,
serum iron, Total Iron Binding Capacity (TIBC), % transferrin saturation, hormone [luteinizing hormone [LH], follicle stimulating hormone [FSH], thyroxine [T4],
thyroid stimulating hormone [TSH], fecal occult and urinalysis) by Week 49.
- Abnormal and clinically relevant changes in liver MRI by Week 45 and physical examinations (including nose and throat mucosal exam and Tanner stage), weight, vital signs, ECG, cardiac MRI or echocardiogram measured LVEF (and other exploratory cardiac endpoints), DXA (bone mineral density), x-ray (bone age) and C-SSRS parameters by Week 49. Cardiac MRI with gadolinium is the preferred method for cardiac imaging. If the subject has a
contraindication to gadolinium, cardiac MRI without gadolinium will be acceptable. Echocardiogram may be substituted if it is not possible to perform cardiac MRI or if
use of echocardiogram is dictated by the local standard of care.
Efficacy:
- Mean change from baseline on the 4 stair climb (4SC) as compared to placebo by Week 49. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Strength and Function:
- Mean change from baseline as compared to placebo on function tests including, Forced Vital Capacity (FVC), Northstar Ambulatory Assessment (NSAA), range of
motion (ROM), Performance of Upper Limb (PUL), 6MWD at Week 17, 33 and 49. Mean change from baseline as compared to placebo on the 4 SC at Week 17 and 33.
- Mean change from baseline as compared to placebo on muscle strength by myometry at Week 17, 33 and 49.
- In subject randomized to sequence 1, mean change from baseline as compared to historical control on functional tests including, 4SC, FVC, NSAA, PUL, 6MWD at Week 97.
- In a pre-specified subset of subjects who may demonstrate a rapid disease decline and with relatively low variability, the mean change from baseline as compared to placebo on function testes including, 4SC, FVC, NSAA, PUL, 6MWD at Week 17, 33 and 49. The definition of this subgroup will be detailed in the Statistical Analysis Plan (SAP).
- In a pre-specified subset of subjects who may demonstrate a rapid disease decline, the mean change from baseline as compared to placebo on muscle strength at Week 17, 33 and 49.
Pharmacodynamic:
- Mean percent change as compared to placebo in muscle volume as measured on MRI by Week 17, 33 and 49. Within subject change from baseline in thigh muscle volume through week 97.
- Noncompartmental GDF-8 parameters such as AUCt(GDF-8), AUCt,ss(GDF-8), CGDF-8(0), Cmax,ss(GDF-8), Tmax(GDF-8), Ctrough,ss(GDF-8), and Css,av (GDF-8), may be determined.
Pharmacokinetic:
- All subjects receiving active drug: Cmax, Tmax, and Ctrough for all visits with PF-06252616 dosing.
- All subjects receiving active drug in Period 1 followed by placebo in Period 2 (Sequence 2): terminal t½ for Visit 19 (last dose in Period 1) using concentration data from samples collected during placebo treatment in Period 2.
- Subjects with additional PK sampling receiving active drug in Period 1: AUCt and Cav for Visits 3, 9, and 15 (first dose of each dose escalation level); AUCt, Cav, and CL for Visits 7, 13, and 19 (last dose of each dose escalation level); for subjects in Sequence 2, also Vss for Visit 19.
Immunogenicity:
Incidence of ADA and neutralizing antibody (NAb) development by Week 97. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 17, 33, 49 through 97. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Australia |
| Bulgaria |
| Canada |
| Italy |
| Japan |
| Poland |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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