Natural History Studies in. Duchenne Muscular Dystrophy. Craig M. McDonald,
MD. Professor and Chair. Physical Medicine & Rehabilitation. Professor of ...
Natural History Studies in Duchenne Muscular Dystrophy Craig M. McDonald, MD Professor and Chair Physical Medicine & Rehabilitation Professor of Pediatrics University of California Davis School of Medicine
Disclosures •
Dr. McDonald has served on Advisory Committees for: • • • •
PTC Therapeutics Acceleron / Shire GSK AVI Biopharma
Loss of Muscle Fiber in DMD:
Normal
3 year old
19 year old (Post-Mortem)
9 year old
•
•
Eagle M, et al. Managing Duchenne muscular dystrophy-the additive effect of spinal surgery and home nocturnal ventilation in improving survival. Neuromuscul Disord. 2007 Jun;17(6):470-5.
DMD Disease Progression DMD patient age, years 0
5
10
15
20
25
30
Developmental Delay Impaired Standing
Progressive Ambulatory Changes
Wheel chair Onset – skeletal deformity Very limited use of arms Ventilation at night Ventilation 24 hours Death
CINRG Natural History Study and Development of Clinical Endpoints in Duchenne Muscular Dystrophy Craig McDonald, MD
www.cinrgresearch.org
CINRG Clinical Sites
CINRG Clinical Site Locations US Sites
International Sites
University Hospitals, Leuven, Belgium
Hadassah, Hebrew University Hospital,
Children’s National Medical Center, Washington, DC
Children's Hospital, Richmond, VA
Children's Hospital of Pittsburgh
Jerusalem, Israel
of UPMC, Pittsburgh, PA
Bloorview Kids Rehab, Toronto, Canada
University of Tennessee, Memphis, TX
Sundaram Medical Foundation, Chennai, India
University of Puerto Rico, San Juan, PR
Royal Children's Hospital, Melbourne, Australia
Washington University - St. Louis, MO
Fundacion Favaloro, Buenos Aires, Argentina
Mayo Clinic, Rochester, MN
Queen Silvia Children's, Göteborg, Sweden
University of California - Davis,
The Children's Hospital at Westmead,
Sacramento, CA
Sydney, Australia
Texas Children's Hospital, Houston, TX
University of Minnesota, Minneapolis, MN
Alberta Children's Hospital, Calgary, Canada
Carolinas Medical Center, Charlotte, NC
University of Alberta, Edmonton, Canada
Children’s Memorial Hospital, Chicago, IL
Centro Clinico NeMO Hospital, Milan, Italy
National Center of Neurology and Psychiatry, Tokyo, Japan
A CINRG Study of the Relationship Between Impairment, Activity Limitation, Participation and Quality of Life in Persons With Confirmed Duchenne Muscular Dystrophy: One-year follow-up of skeletal muscle strength and timed motor performance.
C McDonald1, E Henricson1,, RT Abresch1, J Han1, R Leshner6 E Hoffman6, D Escolar6, A Cnaan6, F Hu6, A Zimmerman6, T Duong6, J Mayhew14, J Florence13, A Arrietta6 and the CINRG Investigators2-20 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
C McDonald , RT Abresch, J Han, E Henricson. UC Davis Medical Center, Sacramento CA V Viswanathan, C Chidambaranathan. Rangarajan Memorial Hospital, Chennai, India D Biggar. Bloorview McMillan Medical Center, Toronto, Canada J Mah. Alberta Children’s Hospital, Calgary, Alberta M Tulinius, B Lindvall. Queen Silvia Children’s Hospital, Göteborg, Sweden R Leshner, D Escolar, E Hoffman, A Cnaan. Children’s National Medical Center, Washington, DC A Kornberg, M Ryan. Royal Children’s Hospital, Melbourne, Australia Y Nevo. Hadassah Hebrew University Hospital, Jerusalem, Israel A Dubrovsky, L Mesa. Instituto de Neurosciencias Fundacion Favaloro, Buenos Aires, Argentina P Clemens, H Abdel-Hamid. Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA K Gorni. Centro Clinico Nemo, Milan, Italy N Kuntz. Mayo Clinic, Rochester, MN A Connolly, A Pestronk, J Florence. Washington University, St. Louis, MO E Monasterio, J Teasley. Children’s Hospital, Richmond, VA T Bertorini, M Igarashi. University of Tennessee, Memphis, TN K North, R Webster. Children’s Hospital at Westmead, Sydney, Australia H Kolski. University of Alberta, Edmonton, Canada J Carlo. University of Puerto Rico, San Juan, PR T Lotze. Texas Children’s Hospital, Houston, TX J Day. University of Minnesota, Minneapolis, MN
Supported by NIH IDDRC P30HD40677, NIH GCRC 5-MO1-RR-020359-04, NIH NCMRR/NINDS 5R24 HD050846, & DOE NIDRR H133B031118.
Selection of Participants Inclusion criteria • 2-4 year olds – require confirmatory diagnostics (complete absence of dystrophin on immunofluorescence or immunoblot, or out of frame deletion in exons 5-60, or gene sequencing showing a point mutation, or out of frame deletion/duplication) and a clinical picture typical of DMD • 5-30 year olds – fulfillment of criteria above, or require documented clinical symptoms of a severe dystrophinopathy and elevated CK >5x normal and an X-linked pedigree with another relative fulfilling criteria listed above. Exclusion criteria • Age at entry cohort is filled (10-20 per age group). • Steroid-treated participants - ambulation past their 16th birthday. • Steroid-naïve participants - ambulation past their 13th birthday.
Methods • Design: Multicenter, international “accelerated” longitudinal observational study • Assessments: Conducted at Baseline, Months 3, 6, 9, 12: – – – – – – –
Clinical History / Review of Systems Anthropometrics / Goniometry MRC MMT / Isometric Strength (CINRG CQMT) Timed Motor Performance Testing (Stand, Stairs, 10M walk) Brooke / Vignos functional assessment scales Pulmonary Function (FVC, FEV1, PEFR, MIP, MEP) Health-Related Quality of Life
• Continuation of assessments annually to at least 5Y will yield ~1700 person-years of data from early childhood to adulthood.
Enrollment by Age and Ambulatory Status
Ambulatory = Able to walk independently, judged by investigator
Cutoff for strength evaluation = able to do 1-person assisted stand-pivot transfer
Glucocorticoid Status at Study Entry
Definition of GC Status
Current User
Prior Use = > 1 month
Naïve = < 1 month and discontinued, or never
This presentation combines Prior/Naive
Timed Function Tests • Stand from Supine • Climb 4 stairs • Walk / Run 10 meters
Time to Run/Walk 10 Meters
+
Clinical Outcomes Time to Walk/Run 10 Meters
Timed 10-Meter Walk (Velocity)
12-Month Change
Whole Population
12-18 Month Risk of Loss of Ambulation based on10-Meter Walk Time
12 Seconds
12-18 Month Risk of Loss of Ambulation based on10-Meter Walk Time
12 Seconds
>12 seconds (No Steroids) McDonald et al. 1995
Time to Event Analysis: (< 10% decline versus > 10% decline in one year
Velocity During 10-Meter Walk/Run vs 6MWD at Baseline
Slide 24
12-18 Month Risk of Loss of Ambulation based on10-Meter Walk Time
12 Seconds
356 Meters 6MWD
Timed function testing in 4-6 Year Olds with DMD >12 sec
< 6 sec
NO Steroids
< 6 sec
+ Steroids
Ability to Stand as a Predictor of Loss of Ambulation (PTC Ataluren Trial) • Lost Standing at baseline
14/30 (46.7%) Lost Ambulation over 48 weeks
• Able to stand at baseline
1/144 (0.7%) Lost Ambulation over 48 weeks
P < 0.0001
PTC Therapeutics, Inc. © 2009 – Slide 27
Prediction of Loss of Standing in 4-6 year olds with DMD
• FDA Clinical Endpoint Qualification Process • “Clinically Meaningful” • Related to Patientreported Outcomes
QMT Knee Extension*
Baseline Distribution
12-Month Change
(Shows differences in steroids, non-steroids)
Range of Stat. Significant 1Y
Decrease
* Previously shown to have the highest correlation with Vignos leg functional grade.
PRO measures and Strength (McDonald et al. Child Neurology 2010) Shriners Hospitals Study: PI M. Sussman
FVC % Predicted
Plans for Natural History Study • Reopen enrollment to all newly diagnosed patients with DMD (or age < 5-6)
Conclusions • Natural history data pertaining to clinically meaningful endpoints (timed function, strength, PFTs and 6 MWT) are aiding in the design of clinical trials in ambulatory boys with DMD • Percent predicted and Z-scores from control data help with maturational issues • Patient-reported outcomes help document the clinical meaningfulness of endpoints
CINRG Members Acknowledgment • • • • • • • • • • • • • • • • • • • • •
University of California, Davis – C. McDonald, E. Henricson, R.T. Abresch, M. Cregan, M. Glicke, J. Han, L. Johnson, N. Joyce, Sundaram Medical Foundation – C. Chidambaranathan, S. Kumar, Holland Bloorview Kids Rehabilitation Hospital– D. Biggar, L. Eliasoph, V. Harris, E. Hosaki, Alberta Children's Hospital – J. Mah, A. Chiu, E. Goia, L. Walker, C. Wright, M. Yousefi, Queen Silvia Children’s Hospital – M. Tulinius, AC. Ahlander, L. Berland, AK. Kroksmark, U. Sterky, Children’s National Medical Center – D. Escolar, R. Leshner, M. Birkmeier, S. Kaminski, K. Parker, C. Spurney, C. Tesi-Rocha, Royal Children's Hospital – A. Kornberg, K. Carroll, K. Devalle, R. Kennedy, M. Ryan, D. Villano, Hadassah Hebrew University Hospital – Y. Nevo, E. Wisband, D. Yaffe, Favaloro Foundation – A. Dubrovsky, J. Corderi, L. Levy, L. Mesa, Mayo Clinic – N. Kuntz, K. Coleman, S. Driscoll, A. Hoffman, W. Korn-Peterson, D. Selcen, IRCCS C Mondino Foundation Hospital – K. Gorni, L. Capone, University of Pittsburgh – P. Clemens, H. Abdel-Hamid, C. Bise, A. Craig, L. Hache, C. Nguyen, Washington University-St. Louis – A. Connolly, J. Florence, B. Malkus, A. Pestronk, R. Renna, J. Schierbecker, C. Siener, C. Wulf, Children's Hospital of Virginia – J. Teasley, S. Blair, B. Grillo, E. Monasterio, University of Tennessee-Memphis – T. Bertorini, J. Clifft, C. Feliciano, M. Igarashi, Children's Hospital at Westmead – K. North, T. Juarez, K. Rose, R. Webster, S. Wicks, University of Alberta – H. Kolski, L. Chen, C. Kennedy, G. Parks, J. Wohlers, University of Puerto Rico – J. Carlo, B. Deliz, S. Espada, P. Fuste, C. Luciano, Texas Children's Hospital – T. Lotze, H. Farber, A. Gupta, S. Habetz, J. Jeffries, R. McNeil, University of Minnesota – J. Day, A. Erickson, M. Margolis, G. Parry, D. Walk, and CINRG Coordinating Center – A. Cnaan, A. Arrieta, N. Bartley, P. Canelos, T. Duong, F. Hu, A, Zimmerman.
Acknowledgements Multicenter Effort US Sites
International Sites
University Hospitals, Leuven, Belgium
Hadassah, Hebrew University Hospital,
Children’s National Medical Center, Washington, DC
Children's Hospital, Richmond, VA
Children's Hospital of Pittsburgh
Jerusalem, Israel
of UPMC, Pittsburgh, PA
Bloorview Kids Rehab, Toronto, Canada
University of Tennessee, Memphis, TX
Sundaram Medical Foundation, Chennai, India
University of Puerto Rico, San Juan, PR
Royal Children's Hospital, Melbourne, Australia
Washington University - St. Louis, MO
Fundacion Favaloro, Buenos Aires, Argentina
Mayo Clinic, Rochester, MN
Queen Silvia Children's, Göteborg, Sweden
University of California - Davis,
The Children's Hospital at Westmead,
Sacramento, CA
Sydney, Australia
Texas Children's Hospital, Houston, TX
University of Minnesota, Minneapolis, MN
Alberta Children's Hospital, Calgary, Canada
Carolinas Medical Center, Charlotte, NC
University of Alberta, Edmonton, Canada
Children’s Memorial Hospital, Chicago, IL
Centro Clinico NeMO Hospital, Milan, Italy
National Center of Neurology and Psychiatry, Tokyo, Japan
Acknowledgements • Funding Department of Education (NIDRR) • NIH (NICHD and NIAMS) • Department of Defense • PPMD • MDA
Executive Summary: Recommendations from the Duchenne Community for the Next Action Plan •
•
“NIH should provide funding for natural history and similar studies that examine the efficacy of certain care standards.” $1.4 million NIAMS grant will add clinically meaningful endpoints to the existing CINRG Natural History study including: • Northstar • 6MWT • Quality of Life measures (NM-PedsQL; NeuroQoL) • Non-ambulatory upper limb measures •
Normative data for all endpoints
203 MDA Clinics Nationwide 5 networked DMD clinical research centers
UC Davis Boston Childrens Hospital Nationwide Childrens Hospital Washington University University of Minnesota
MDA’s DMD Clinical Research Network
5 sites
Boston Childrens’ Hospital
Nationwide Childrens’ Hospital (Ohio State)
Washington University
University of Minnesota
UC Davis
Studies to support evidence-based standards of care
Develop outcome measures for the clinical trials of DMD
Conduct clinical trials
Enhance communication and collaboration among MDA clinics
MDA Clinical Research network Studies
Cardiac Natural History Study
Non-Ambulatory Endpoints
Lisinopril vs. Losartan Trial
Infant clinical endpoints
6 Minute Walk Test as a Clinical Endpoint in DMD Craig McDonald, MD Professor and Chair Physical Medicine & Rehabilitation University of California Davis Medical Center Sacramento, CA
Background of Ambulation Evaluation in DMD • Walking Speed previously shown to correlate with efficiency of locomotion (McDonald et al. 1998)
Time Distance Parameters in Gait • Velocity = Stride Length X Cadence • Stride Length = Distance between two successive placements of the same limb • Cadence = Steps / Minute
Gait in DMD with Disease Progression • Reduced Stride Length • Widening of the base of support as measured by increased stride width
• Decreased cadence (Steps /Min)
Sutherland DH, et al. Dev Med Child Neurol; 198123:3-22. D'Angelo MG, et al. Gait Posture 2009;29:36-41.
Modification of the ATS Guidelines for the 6MWT specifically for children with DMD (UC Davis) • Standard procedures for conduct of the test have been developed • Standard Videotape explaining the conduct of the test is shown to all subjects before testing begins • Standardized linear course with traffic cones 25 meter apart used (practical for most clinical settings) • Line down middle of course and arrows around cones provide visual feedback to subjects • Constant encouragement is provided to the child in addition to feedback at one minute intervals of time remaining on the test • One clinical evaluator trails the subject to assist in the event of a fall and mark the distance achieved at one minute increments • Time and distance that falls occur are measured
PTC Therapeutics, Inc. © 2009 – Slide 48
6-Minute Walk Distance vs Stride Length
Screen/Baseline (~ 4-6 Weeks Apart) of 6Minute Walk Distance in Boys with DMD in PTC Study 007
Velocity During 10-Meter Walk/Run vs 6MWD at Baseline
Slide 51
DMD
Control
DMD Percent of Control
6MWD
366
621
(M)
+ 83
+ 68
Stride Length (M)
0.9
1.5
+ .16
+ .24
Cadence
130
142
(Steps/Min)
+ 16
+ 16
59%
60%
91%
Natural History of 6MWT Findings in DMD Observational Study
Ataluren trial N= 57
Italian Dataset (Eugenio Mercuri)
6MWD Results Showed Low-Dose Ataluren Slowed Loss of Walking Ability Compared to Placebo* Low-Dose vs. Placebo Mean Difference at Week 48: + 29.7 m
ITT p = 0.0584 PP p = 0.0462
Delta = 29.7 m
High-Dose vs. Placebo Mean Difference at Week 48: + 0.8 m
ITT p = 0.9788 PP p = 0.9412
* Post hoc analysis Slide 55
ITT: Intent to treat PP: Per protocol
% Change in 6MWT
Baseline
12 month
Δ Meters
% Change
623
636
+ 13 m
+ 2.1%
357
300
- 57 m
- 15.9%
Ataluren Placebo
359.6
317.4
- 42.6 m
- 11.8%
Ataluren Low dose
350.0
342.7
- 12.9 m
- 3.7%
Healthy Controls Study 013
UC Davis Observational Study 013
Slide 56
Observed mean change in % Predicted 6MWD
CONFIDENTIAL
© 2011 – Slide 57
Slide 57 © 2011 PTC Therapeutics, Inc.
Analysis of % Predictive 6MWD at Week 48 Ataluren trial
Low Dose vs Placebo
High Dose vs Placebo
Delta
p
Delta
p
5.40 %
0.0118
0.00 %
0.9982
*Refined MMRM, not adjusted for multiplicity
CONFIDENTIAL
© 2011 – Slide 58
Slide 58 © 2011 PTC Therapeutics, Inc.
Weeks to Loss of Ambulation
6MWD as a Predictor of Loss of Ambulation (PTC ataluren trial)
Baseline 6MWD in DMD subjects who lost ambulation
Time to Risk of Loss of Ambulation (< 320 meters on 6MWT)
Ataluren
Percent Change
Baseline
12 months
24 months
36 months
Time to Risk
-3.7%
356
343
330
318
3 years
- 11.8%
356
314
Low dose
Placebo
Slide 60
1 year
Time to Risk of Loss of Ambulation (Based on Improvement in per year % Predicted of 5%) Percent Predicted
Baseline
Time to 33% Mean for Loss of Amb Group
Time to 50% Threshold
356
5 years
2 years
Ataluren
Ataluren
Baseline All Patients
Lost Amb in 1 year
60%
33%
