A Trial of PF-06252616 in Ambulatory Participants With LGMD2I

Study Description

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Brief Summary:

The investigational product PF 06252616, a humanized anti myostatin monoclonal antibody that neutralizes myostatin (GDF8) is in development for the treatment of Limb Girdle Muscular Dystrophy 2I (LGMD2I) to preserve and/or improve muscle function.

This study will provide the clinical assessment of the safety, tolerability, Pharmacokinetics and Pharmacodynamics of PF 06252616 following repeat IV doses in ambulatory adults with LGMD2I.

Condition or disease	Intervention/treatment	Phase
LGMD2I	Drug: PF 06252616	Phase 1; Phase 2

Detailed Description:

This study is a Phase 1b/2, open-label multiple ascending dose escalation study to evaluate the safety, tolerability, efficacy, PK and PD of PF 06252616 in ambulatory adults with LGMD2I. The study design is intended to determine the optimal safe and pharmacologically active dose of PF 06252616 in LGMD2I while providing an opportunity for all subjects to receive active drug for a rare and disabling disorder. The study will be conducted in three periods: Lead-In, Treatment and Follow-up periods. The Lead-In and Follow-up periods will each be 16 weeks to allow an assessment of the change of various outcome measures of this period of time and comparison of change in function before, during and after treatment. The Treatment period will be 32 weeks. Three cohorts of participants will be enrolled and receive escalating doses of PF 06252616. The first cohort will have the option to crossover to the highest dose.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	19 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1b/2, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Participants With LGMD2I
Study Start Date :	July 2016
Estimated Primary Completion Date :	August 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Low Dose, Cohort 1; 4 subjects will be enrolled in cohort 1 and will receive an initial dose of 5mg/kg PF 06252616 IV every 4 weeks. Following 32 weeks of treatment and a safety review, if no stopping rules have been met, subjects will be receive an additional 32 weeks of treatment with 40 mg/kg PF 06252616 IV every 4 weeks.	Drug: PF 06252616
Active Comparator: Middle dose, Cohort 2; 8 subjects will be enrolled in cohort 2 and receive 20 mg/kg of PF 06252616 IV every 4 weeks for 32 weeks.	Drug: PF 06252616
Active Comparator: High dose, Cohort 3; 8 subjects will be enrolled in cohort 3 and receive 40 mg/kg of PF06252616 IV every 4 weeks for 32 weeks.	Drug: PF 06252616

Outcome Measures

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Primary Outcome Measures :

1. Incidence of dose limiting or intolerability treatment related AEs [ Time Frame: Baseline through 96 weeks ]

Secondary Outcome Measures :

1. Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of GDF-8 [ Time Frame: Baseline through 96 weeks ]
2. Area Under the Curve, steady state from Time Zero to end of dosing interval (AUCtau,ss) of GDF-8 [ Time Frame: Baseline through 96 weeks ]
3. Maximum Observed Serum Concentration at steady state (Cmax, ss) of GDF-8 [ Time Frame: Baseline through 96 weeks ]
4. Mean change from baseline in 10 meter walk/run time in seconds [ Time Frame: Baseline through 96 weeks ]
5. Mean change from baseline of Forced Vital Capacity in Liters [ Time Frame: Baseline through 96 weeks ]
6. Time to Reach Maximum Observed Serum Concentration (Tmax) of GDF-8 [ Time Frame: Baseline through 96 weeks ]
7. Observed Serum Trough Concentration at steady state (Ctrough,ss) of GDF-8 [ Time Frame: Baseline through 96 weeks ]
8. Observed Serum Concentration steady state average (Css,av) of GDF-8 [ Time Frame: Baseline through 96 weeks ]
9. Maximum Observed Serum Concentration (Cmax) of PF-06252616 [ Time Frame: Baseline through 96 weeks ]
10. Time to Reach Maximum Observed Serum Concentration (Tmax) of PF-06252616 [ Time Frame: Baseline through 96 weeks ]
11. Minimum Observed Serum Trough Concentration (Ctrough) of PF-06252616 [ Time Frame: Baseline through 96 weeks ]
12. Serum Decay Half-Life (t1/2) of PF-06252616 [ Time Frame: Baseline through 96 weeks ]
13. Immunogenicity: Incidence of anti-drug antibody [ Time Frame: Baseline through 96 weeks ]
14. Immunogenicity: Incidence of neutralizing antibody [ Time Frame: Baseline through 96 weeks ]
15. Mean change from baseline in 2MWD in meters [ Time Frame: Baseline through 96 weeks ]
16. Mean change from baseline in TUG in seconds [ Time Frame: Baseline through 96 weeks ]
17. Mean change from baseline in muscle strength as measured by modified MRC scale [ Time Frame: Baseline through 96 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 99 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Male and female patients age ≥ 18
2. Diagnosis of LGMD2I as defined by clinical presentation consistent with LGMD2I and FKRP gene testing showing biallelic alterations known or likely to be pathogenic. 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).
3. Ability to walk/run 10m
4. Ability to rise from chair
5. Adequate hepatic and renal function on screening laboratory assessments
6. Iron content estimate on the screening liver MRI within the normal range as determined by R2* value (R2* ≤ 139 Hz at 3.0T).
7. Participant must provide written informed consent for participating in study.
8. Participant must possess the ability, per the Principal Investigator (PI), to understand and comply with protocol instruction for the entire duration of the study.

Exclusion Criteria:

1. Known cognitive impairment or behavioral issues that would impede the ability to provide informed consent or to follow study 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 consent. Prior lower limb fractures must be fully healed and at least 3 months from injury dates.
4. Previous treatment with another investigational product within 30 days or 5 half-lives, (whichever is longer) prior to consenting.
5. Corticosteroid treatment within 3 months prior to consenting.
6. Compromised cardiac function (left ventricular ejection fraction <50%).
7. Unwilling or unable (e.g. metal implants, requires sedation) to undergo examination with closed MRI without sedation.
8. History of allergic or anaphylactic reaction to a therapeutic or diagnostic protein.
9. Female subjects who are pregnant or nursing.
10. Subjects who, are biologically capable of having children who are unwilling or unable to use highly effective methods of contraception (as outlined in this protocol) during sexual activity for the duration of the study and through completion of final study visit.
11. Predisposition to iron accumulation. (Serum iron >1.2 X ULN, serum ferritin >1.2 ULNN).
12. Underlying disposition for bleeding disorder on screening laboratory assessment (PT/INR>1.25 X ULN, aPTT > 1.25 ULN, fecal occult blood is positive)
13. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurologic, or allergic disease.
14. Unwillingness or inability to comply with the requirements of this protocol (in the opinion of the PI) including, but not limited to, the presence of any condition (physical, mental, or social) that is likely to affect the participant's ability to return for study visits or adhere to the visit schedule.

Contacts and Locations

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Locations

United States, Maryland
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
Baltimore, Maryland, United States, 21205

Sponsors and Collaborators

Kathryn Wagner

Pfizer

Investigators

Principal Investigator:	Kathryn R Wagner, MD/PhD	Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

More Information

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Responsible Party:	Kathryn Wagner, Director, Center for Genetic Muscle Disorders, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ClinicalTrials.gov Identifier:	NCT02841267 History of Changes
Other Study ID Numbers:	WI203720
First Posted:	July 22, 2016
Last Update Posted:	August 23, 2017
Last Verified:	August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No