Ataluren (PTC124®) in Nonambulatory Patients With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy (nmDMD/BMD)
I realize it is so difficult to see trials targeting specific mutations and feel like you are on the outside looking in, wondering when it will be your son’s turn. Prosensa and AVI’s trials are moving forward as well. More trials are in the planning stages – Sildenafil, Losartin, IGF-1 and others. Still some of our boys do not fit the criteria, either based on mutation or because they are not walking.
So this trial fills a hole. It is a safety trial but will validate outcome measures for the non-ambulatory boys. Outcome measures in the non-ambulatory population have been a significant barrier for inclusion in clinical trials and for this reason, trials have focused on ambulatory boys. How to measure? What to measure?
There has been considerable discussion about cardiac and pulmonary outcome measures, clinicians concerned about the length of time required to demonstrate decrease, stabilization or benefit.
While the Ataluren trial will include cardiac and pulmonary endpoints, it will include a variety of functional measures, assuming one or more will be validated as THE outcome measure(s) for the non-ambulatory population.
And then, at the end of the day, non-ambulatory boys will not feel like they are at the end of the line.
For more on this trial, click here.
Tuesday, December 15, 2009
Friday, December 11, 2009
Congratulations to Annemieke Aartsma-Rus
You may have met Annemieke at the PPMD conference. She is wonderful and brilliant and committed to our sons.
NWO has awarded Vidi-grants to outstanding research and researchers: Annemieke Aartsma-Rus of Leiden LUMC The Netherlands wins the prize!
The Dutch Organization for Scientific Research (NWO) has awarded 89 young, innovative scientists a so-called Vidi-grant. Each researcher will receive a grant amounting up to 800,000 euro aimed at developing an own line of research and also establishing a research team for a period of five years. In total NWO will distribute more than 70 million euros to the winners.
Vidi is targeting outstanding researchers who have done successful research after the PhD. The researchers proved their capabilities to come up with innovative ideas and bringing them successfully and independently into a development stage. The scientists are among the best ten to twenty percent in their field. With the Vidi-grant they can do further research and establish a research team for a period of five years.
Annemieke Aartsma-Rus, working at the Department of Human Genetics Leiden LUMC, is honored with this Vidi-grant. Our supporters do know Annemieke not only for the great research she does towards a cure for Duchenne, but also of her lectures at Duchenne conferences, where she is able to explain results of academic research in layman's terms.
Annemieke is planning to spend the money in the following research area:
Genes do consist of exons (carrying protein information) and introns (not carrying protein information). Before a protein can be made from a gene, there is just a copy of the gene (RNA) being made. Thereafter, in the process called splicing, introns are being cut and exons are put together. The exon skip therapy invades the splicing process (ensuring one exon is left out). As the DMD gene is very large, limited knowledge exists regards to a smooth splicing process. Recently, a new method has become available for analyzing this major gene ultimately resulting in better insight into the splicing process of DMD. This will contribute to further optimization of exon skipping and potentially more complex exon skip applications (e.g. multiexon skipping and exon skipping for duplications) could be developed.
We are pleased and very proud of Annemieke and congratulate her warmly with this outstanding achievement.
NWO has awarded Vidi-grants to outstanding research and researchers: Annemieke Aartsma-Rus of Leiden LUMC The Netherlands wins the prize!
The Dutch Organization for Scientific Research (NWO) has awarded 89 young, innovative scientists a so-called Vidi-grant. Each researcher will receive a grant amounting up to 800,000 euro aimed at developing an own line of research and also establishing a research team for a period of five years. In total NWO will distribute more than 70 million euros to the winners.
Vidi is targeting outstanding researchers who have done successful research after the PhD. The researchers proved their capabilities to come up with innovative ideas and bringing them successfully and independently into a development stage. The scientists are among the best ten to twenty percent in their field. With the Vidi-grant they can do further research and establish a research team for a period of five years.
Annemieke Aartsma-Rus, working at the Department of Human Genetics Leiden LUMC, is honored with this Vidi-grant. Our supporters do know Annemieke not only for the great research she does towards a cure for Duchenne, but also of her lectures at Duchenne conferences, where she is able to explain results of academic research in layman's terms.
Annemieke is planning to spend the money in the following research area:
Genes do consist of exons (carrying protein information) and introns (not carrying protein information). Before a protein can be made from a gene, there is just a copy of the gene (RNA) being made. Thereafter, in the process called splicing, introns are being cut and exons are put together. The exon skip therapy invades the splicing process (ensuring one exon is left out). As the DMD gene is very large, limited knowledge exists regards to a smooth splicing process. Recently, a new method has become available for analyzing this major gene ultimately resulting in better insight into the splicing process of DMD. This will contribute to further optimization of exon skipping and potentially more complex exon skip applications (e.g. multiexon skipping and exon skipping for duplications) could be developed.
We are pleased and very proud of Annemieke and congratulate her warmly with this outstanding achievement.
Care Considerations Available
Care Considerations – to be published in Lancet – is available now, online . These Care Considerations set the stage for all boys everywhere to receive optimal care. Families now have access to this document as well as an abbreviated, family-friendly version currently in development. This is your guide and your doctor's guide to good care. Your questions, your concerns are addressed. You now have published evidence about what is best for your son. You no longer have to fight the good fight to obtain good care. Today, it’s here and while some of you may believe in a more aggressive approach, this document reflects what ALL experts agree upon. It is a consensus document.
Victor Dubowitz is famous for saying ‘boys are not mice’ and what happens in the mouse may not exactly translate. In other words, we (researchers) can cure mice, but the task becomes more difficult as you move up the ladder – rodent –dog –monkey – human.
And who hasn’t had millions of Google Alerts about mice? And afterward conversations with a researcher who disagrees with the information. Frustrating! And why? Because animal testing is not standardized.. until now. In mice clinical trials, they had no standard of care! Meetings were recently held to develop SOP (standard operating procedures) for research/animal testing. Otherwise we are not comparing apples to apples.
It’s the same for our sons. Care varies across the US and across the world. It is important to ‘level the field’, to ensure all boys have access to standardized care, which is necessary to improve outcomes today for clinical trials tomorrow.
When Chris and Patrick were here, state of the art care consisted of 5 words “no hope and no help.” Boys with Duchenne stopped walking at 8 or 9. Physicians did not perform baseline studies and no one mentioned bone density. Night splints (AFO’s) and stretching were not recommended. Muscle biopsies were done to confirm diagnosis (the absence of dystrophin). Genetic testing was not on the map. And families were alone…there was no internet.
Today, thanks to your advocacy efforts, we now have Care Considerations, a document of expert consensus about Care – what it should look like, how often to review, what tests, what medicines to add and when. It discusses the need for multidiscipline care (coordinated care that involves many subspecialists), the need for genetic testing and participation in registries. It lays down a basis for good care. This in turn prepares our sons for clinical studies and for researchers, clinicians, and industry to appropriately determine benefit and get therapies approved.
Improved care translates into improved quality of life and extended life span. It provides all of us – researchers and clinicians a level of confidence about care. It also highlights gaps – things we need to think about and improve our base of knowledge.
Print a copy of this document, keep it handy. Use it for reference, for emergencies. Use it for information, for evidence. You now have the back-up you need to ensure your son receives the best care possible and (cross your fingers and pray) the opportunity to participate in promising clinical trials.
Victor Dubowitz is famous for saying ‘boys are not mice’ and what happens in the mouse may not exactly translate. In other words, we (researchers) can cure mice, but the task becomes more difficult as you move up the ladder – rodent –dog –monkey – human.
And who hasn’t had millions of Google Alerts about mice? And afterward conversations with a researcher who disagrees with the information. Frustrating! And why? Because animal testing is not standardized.. until now. In mice clinical trials, they had no standard of care! Meetings were recently held to develop SOP (standard operating procedures) for research/animal testing. Otherwise we are not comparing apples to apples.
It’s the same for our sons. Care varies across the US and across the world. It is important to ‘level the field’, to ensure all boys have access to standardized care, which is necessary to improve outcomes today for clinical trials tomorrow.
When Chris and Patrick were here, state of the art care consisted of 5 words “no hope and no help.” Boys with Duchenne stopped walking at 8 or 9. Physicians did not perform baseline studies and no one mentioned bone density. Night splints (AFO’s) and stretching were not recommended. Muscle biopsies were done to confirm diagnosis (the absence of dystrophin). Genetic testing was not on the map. And families were alone…there was no internet.
Today, thanks to your advocacy efforts, we now have Care Considerations, a document of expert consensus about Care – what it should look like, how often to review, what tests, what medicines to add and when. It discusses the need for multidiscipline care (coordinated care that involves many subspecialists), the need for genetic testing and participation in registries. It lays down a basis for good care. This in turn prepares our sons for clinical studies and for researchers, clinicians, and industry to appropriately determine benefit and get therapies approved.
Improved care translates into improved quality of life and extended life span. It provides all of us – researchers and clinicians a level of confidence about care. It also highlights gaps – things we need to think about and improve our base of knowledge.
Print a copy of this document, keep it handy. Use it for reference, for emergencies. Use it for information, for evidence. You now have the back-up you need to ensure your son receives the best care possible and (cross your fingers and pray) the opportunity to participate in promising clinical trials.
Notes from UPPMD Endocrine Meeting: Florence, Italy - October 28 & 29
Care and treatment in Duchenne muscular dystrophy is evolving with improved treatments and promising therapies on the horizon. Parents and young men need to be proactive about care, to understand what to do, what can be done and the appropriate time for intervention. Risk/benefit analysis must be thoroughly and carefully evaluated. It is our responsibility as a community to act as advocates for our sons in order to improve current therapies, to address gaps in care, and to accelerate the development new treatments and one day, a cure.
The “Care Considerations” document is expected to be published in “LANCET” in the January and February issue. Using the Rand method, this document has been written to serve as a guide for optimal care. For some of you, there will be no surprises. The relevance of the document is to set standards for boys/young men and their parents all over the world, hopefully improving care in areas where knowledge and expertise is limited.
In the area of use of steroids in Duchenne, steroids are considered ‘gold standard’ but there is no consensus on the best regimen or timing of the intervention. The Care Considerations recommendations for intervention suggest a steroid regimen should be started when there is a plateau in strength. There are significant variations in the field with some physicians recommending a more aggressive approach. The document is not an endpoint, rather a beginning, setting the stage for what we know about care today and will be updated as new knowledge and therapies become available.
While steroids are now widely used, there is an urgent need to address the side effects of chronic steroid use. United Parent Projects Muscular Dystrophy (UPPMD) – is committed to work with experts to fill these gaps in care; to understand the issues and concerns; and to work with clinicians and subspecialists to understand what we know and what we will need to know and do in order to improve care. UPPMD members and Tony Huynh (Endocrinologist from Australia, son with Duchenne) organized a workshop to promote dialogue and discussion of Endocrine issues in Duchenne. The meeting was held October 28 and 29 in Florence, Italy.
Endocrine issues in Duchenne include:
o Bone Health – Bone Density in Duchenne is abnormal at diagnosis. Steroids have additional negative effect on bone density.
o Growth Delay – Boys with Duchenne are shorter than their healthy peers. Steroids further impact this growth delay.
o Delayed Puberty – Delayed puberty or complete suppression of puberty is seen with steroid use.
o Insulin Resistance – Chronic steroid use can lead to weigh gain and insulin resistance.
Putting the issues on the table:
Initial Question – what would you do if your 13 y/o son arrived home from his school, in tears, because he looked so different from his peers – shorter, pre-pubescent, facial distortion and overweight. What would you do?
As a community, it is unacceptable to put that question on hold for several years while clinical trials are developed and even more years before the data is available and decisions made. While we appreciate and agree that evidence based medicine is the gold standard, is there a middle ground, an approach we might take to work together to sort out some of these questions in a timely to help this generation of boys in an effort to limit side effects of chronic steroid use, improve self-esteem, and quality of life?
Duchenne is complex multi-system condition and answers are not straightforward. We have learned a great deal about mutations and the in-frame/out-of-frame rule, and while the rule works some of the time, not all boys follow the rules. There are genetic modifiers that influence and alter progression. There are significant challenges to testing compounds in the Duchenne population and proving benefit (or not).
The initial discussion of the UPPMD workshop on Endocrine issues focused on steroid dose. There was general agreement on the dose .75mg/kg Prednisone and .9mg/kg Deflazacort. Some of the physicians adjust dose as size/weight increase, while others make no changes to the initial recommended dose. While there is no comparative data, some physicians suggested their patients have less side effects when the dose is not adjusted (increased), rather the initial dose was maintained over time.
SESSION 1 – GROWTH
In many presentations on use of steroids, physicians suggest ‘shorter is better’. Diana Escolar used principles of physics on force and resistance to demonstrate ‘shorter is better’ in terms of muscle strength. But the question is not simple. Is shorter better psychologically? Are the boys (not their parents) ok with short stature? Boys with Duchenne are already destined to be shorter than their healthy peers. Publications suggest that Duchenne boys have normal weight and height, but delays in growth begin during their first years of life. Craig McDonald’s paper suggested the median height of Duchenne is significantly less (<50th percentile) than their healthy peers by age 10. The question remains – Is short stature a detriment in Duchenne? There is no data to support functional or psychological detriment of short stature in Duchenne and there is very little information available, only several case reports. Based on the available data, no recommendations regarding treatments can be made for treating short stature in Duchenne.
Meilan Rutter discussed her experience in Cincinnati. To date, she has evaluated 30 boys with growth failure. The boys have been followed up for 6 months to 2 years. All are on long term steroids and the ages range from 9-17 years. 26 of the 29 boys had low or borderline GH levels. Using GH, the height/growth velocity increased from the rate of 1 cm/year to an average of 5 cm/year. Dr. Rutter suggested that this experience has NOT been completely analyzed, that more work is needed. The long term effect is not known.
• Evidence suggests that Duchenne does influence height and that short stature is not detrimental to function
• Data is lacking on actual psychological impact of height restriction due to steroids and interaction of other factors (cushionoid appearance, pubertal delay)
Assessment
o Linear height is not trivial
o Standards need to be laid out and disseminated for measuring height
o National specific growth charts need to be used
o Need to determine how GH is to be measured.
Height data could be added to the current data collection natural history collaboration with Treat NMD and other groups.
If assessments of GH are possible could they be addressed as an add-on to the upcoming Treat NMD steroid trial?
It was generally thought that a retrospective look may have quality issues and may not provide useful information. The participants recommended Dr. Rutter’s data be thoroughly analyzed and may provide a starting point.
Intervention
o GH data need to be assessed both in respect to height gain and strength/function
o Timing of intervention need to be determine
o Concern that this intervention will necessarily be individualized rather than a standardized treatment
o Pilot data may be interesting/informative from Cincinnati cohort already treated
o TACT review of potential for trial (June meeting)
SESSION 2 – PUBERTY
High dose steroids result in delayed or arrested puberty. Cincinnati Children’s has 486 boys in their database. 60 boys ages 13 and older were given pubertal exams and tested for testosterone levels. 16 of these young men were not included in the case study because they were adults and on low or an intermittent dose of steroids. 43/44 of these young men had no evidence of puberty. Their testosterone levels were undetectable. All of the young men had small penises. 15 of the boys have been treated with 1/month injections of testosterone. By adulthood, young men would be on testosterone regimens every two weeks. In some cases AndroGel (topical testosterone) was used.
Young men treated with testosterone have experienced changes related to puberty – increased facial hair, increased size of penis, changes in facial distortion.
Assessment
• Pubertal delay or complete suppression of puberty is seen with prolonged steroid use.
• Testosterone replacement is possible.
• No concerns expressed with testosterone replacement.
• Guidelines are needed to include assessments and timing of interventions.
Intervention
• Testosterone (AndroGel)
SESSION 3 – BONE HEALTH
Published evidence suggests, children with Duchenne have an increased risk of fracture which is exacerbated by chronic steroids use. C. McDonald’s paper suggested that Duchenne boys who do not take steroids have a high incidence of fracture. W. King’s paper noted 32% have vertebral fractures in steroid group and an increased risk (2.6X) of long bone fractures. Bothwell predicted a 75% risk of fracture following 100 months of steroids use.
The effect of steroids and Duchenne on bone are complex. While steroids affect the rate of bone growth and therefore bone mass, immobility adds to the reduction in bone mass. In addition, it is difficult to establish consensus/clear guidance on how to measure bone mineral density and how to interpret results. Boys with Duchenne, even those who do not use steroids, have low bone mineral density and the bone mineral content does not increase normally with age.
Bisphosphonate treatment is indicated when a vertebral fracture is present to reduce acute pain and to preserve bone density in the future. There is no agreement on prophylactic treatment.
UK consensus statement applied across 19 centers recommends DXA scans annually at the start of steroids and Vitamin D levels. The statement includes the recommendation to treat vertebral fractures with IV Bisphosphonate.
Kate Bushby recommends Risedronate 35mg; calcium 500mg. and Vitamin D 400 U. to her patients on daily steroids. Side effects are monitored to include dental prophylactics, urinary calcium/creatine rati, and DXA every 12 months.
Bone health in Duchenne is a challenge. Challenges include:
• Cumulative dose of (at least daily) steroid regimes to have an impact on bone health and can lead to painful vertebral fractures which can limit ambulation.
• Can we optimize steroid regimes to minimize risks while maintaining functional benefit?
• Can we decide on a rational regimen for prophylaxis?
• Does this require Randomized Clinical Trials (RCT)?
• Is it acceptable to provide interim guidance as the burden of steroid treatment in the community increases?
• Bone health is complex, the elements include: density/strength/quality.
• DXA considered gold standard for measuring Becker muscular dystrophy.
• In Duchenne, the increased risk of fracture is 5% per year
• Pediatric position 2007 – only Z score should be considered. Is this sufficient in Duchenne?
Assessment
• Relationship emerging between DXA data and fracture risk in children.
• There is increasing experience of bisphosphonates in children and in the Duchenne population in particular
• Randomized Clinical Trial (RCT) is planned for trial in Australia. Are others needed?
• Need guidelines for assessment and prophylaxis.
• Vitamin D needs to be measured and supplemented.
Interventions
• Calcium, Vitamin D
• Bisphosphonates
SESSION 4 – WEIGHT GAIN
The impact of increased weight in Duchenne includes carbohydrate intolerance, diabetes, heart disease, impaired lung function, decreased mobility, further weight gain, increased osteoporosis, poor self-image, increased caregiver burden, and quality of life for everyone. While it is easy to say ‘calories in, calories out’, the issue is complex. Clinical evaluation on growth must be evaluated. This should be accompanied by dietary evaluation and screening labs (fasting glucose, including HbA1c) and in some cases GTT. Options include altering steroid dose and regimen, improved diet (exercise), and medications. Metformin is an insulin sensitizing agent that improves weight and insulin resistance in patients with diabetes and excessive weight. Recommended dose is 1000-2000mg/day.
In Cincinnati, 15 boys have been treated with Metformin. Most had normal glucoses. ALL had insulin resistance. Metformin was used as an adjunctive treatment in addition to diet. 13/15 boys lost weight with improved self-esteem and quality of life.
Assessment
• Weight gain
• Dietary Evaluation
• Screening blood tests
• Need to establish threshold for GTT
Intervention
• Diet/Education – Consider Weight Watchers or similar
• 75-80% normal intake for ambulant boys
• Non-ambulant 60-75%
• Consider Metformin for those with proven insulin resistance and extreme weight gain.
• Are there straightforward guidelines from other specialties or adult practice?
STOPPING STEROIDS – Steroid Withdrawal
The main effect of glucocortoid is suppression of adrenal glands. This suppression results in feedback to the pituitary and hypothalamus and results in decreased CRH and ACTH). High doses or too much glucocorticoid is associated with cushionoid syndrome and chronic steroid administration results in hypothalamus – pituitary adrenal suppression, which is dose, duration, and mode dependent. Withdrawal from a steroid regimen has to be done in consultation with your physician.
Recommended way to withdraw from steroid:
1. Reduce dose by 25% on a 1-2 wk, basis.
2. When at physiological dose switch to equivalent dose of hydrocortisone 12mg/m2/day.
3. Decrease by 2 ½ mg/wk.
4. Emergency care guidelines in place.
One KEY point is that the circadian rhythm recovers first.
Assessments
• Stress testing after a year of steroids.
• Need more data in this specific condition (antibody response to immunization, stress response).
Interventions
• Emergency guidelines need to be reinforced.
Participants in the meeting:
Tony Hunyh (Endocrinologist, Australia)
Meilan Rutter (Endocrinologist, USA)
Maria Luisa Bianchi (Endocrinologist, Italy)
Peter Hindemarsh (Endocrinologist, UK)
Kate Bushby (Clinical Genetics, Newcastle)
Kevin Flanigan (Neurologist, USA)
Doug Biggar (Pediatrician, Canada)
Brian Tseng (Neurologist, USA)
Diana Escolar (Neurologist, USA)
Larry Markham (Cardiologist, USA)
Chris Condin (Anthropologist, Canada)
The “Care Considerations” document is expected to be published in “LANCET” in the January and February issue. Using the Rand method, this document has been written to serve as a guide for optimal care. For some of you, there will be no surprises. The relevance of the document is to set standards for boys/young men and their parents all over the world, hopefully improving care in areas where knowledge and expertise is limited.
In the area of use of steroids in Duchenne, steroids are considered ‘gold standard’ but there is no consensus on the best regimen or timing of the intervention. The Care Considerations recommendations for intervention suggest a steroid regimen should be started when there is a plateau in strength. There are significant variations in the field with some physicians recommending a more aggressive approach. The document is not an endpoint, rather a beginning, setting the stage for what we know about care today and will be updated as new knowledge and therapies become available.
While steroids are now widely used, there is an urgent need to address the side effects of chronic steroid use. United Parent Projects Muscular Dystrophy (UPPMD) – is committed to work with experts to fill these gaps in care; to understand the issues and concerns; and to work with clinicians and subspecialists to understand what we know and what we will need to know and do in order to improve care. UPPMD members and Tony Huynh (Endocrinologist from Australia, son with Duchenne) organized a workshop to promote dialogue and discussion of Endocrine issues in Duchenne. The meeting was held October 28 and 29 in Florence, Italy.
Endocrine issues in Duchenne include:
o Bone Health – Bone Density in Duchenne is abnormal at diagnosis. Steroids have additional negative effect on bone density.
o Growth Delay – Boys with Duchenne are shorter than their healthy peers. Steroids further impact this growth delay.
o Delayed Puberty – Delayed puberty or complete suppression of puberty is seen with steroid use.
o Insulin Resistance – Chronic steroid use can lead to weigh gain and insulin resistance.
Putting the issues on the table:
Initial Question – what would you do if your 13 y/o son arrived home from his school, in tears, because he looked so different from his peers – shorter, pre-pubescent, facial distortion and overweight. What would you do?
As a community, it is unacceptable to put that question on hold for several years while clinical trials are developed and even more years before the data is available and decisions made. While we appreciate and agree that evidence based medicine is the gold standard, is there a middle ground, an approach we might take to work together to sort out some of these questions in a timely to help this generation of boys in an effort to limit side effects of chronic steroid use, improve self-esteem, and quality of life?
Duchenne is complex multi-system condition and answers are not straightforward. We have learned a great deal about mutations and the in-frame/out-of-frame rule, and while the rule works some of the time, not all boys follow the rules. There are genetic modifiers that influence and alter progression. There are significant challenges to testing compounds in the Duchenne population and proving benefit (or not).
The initial discussion of the UPPMD workshop on Endocrine issues focused on steroid dose. There was general agreement on the dose .75mg/kg Prednisone and .9mg/kg Deflazacort. Some of the physicians adjust dose as size/weight increase, while others make no changes to the initial recommended dose. While there is no comparative data, some physicians suggested their patients have less side effects when the dose is not adjusted (increased), rather the initial dose was maintained over time.
SESSION 1 – GROWTH
In many presentations on use of steroids, physicians suggest ‘shorter is better’. Diana Escolar used principles of physics on force and resistance to demonstrate ‘shorter is better’ in terms of muscle strength. But the question is not simple. Is shorter better psychologically? Are the boys (not their parents) ok with short stature? Boys with Duchenne are already destined to be shorter than their healthy peers. Publications suggest that Duchenne boys have normal weight and height, but delays in growth begin during their first years of life. Craig McDonald’s paper suggested the median height of Duchenne is significantly less (<50th percentile) than their healthy peers by age 10. The question remains – Is short stature a detriment in Duchenne? There is no data to support functional or psychological detriment of short stature in Duchenne and there is very little information available, only several case reports. Based on the available data, no recommendations regarding treatments can be made for treating short stature in Duchenne.
Meilan Rutter discussed her experience in Cincinnati. To date, she has evaluated 30 boys with growth failure. The boys have been followed up for 6 months to 2 years. All are on long term steroids and the ages range from 9-17 years. 26 of the 29 boys had low or borderline GH levels. Using GH, the height/growth velocity increased from the rate of 1 cm/year to an average of 5 cm/year. Dr. Rutter suggested that this experience has NOT been completely analyzed, that more work is needed. The long term effect is not known.
• Evidence suggests that Duchenne does influence height and that short stature is not detrimental to function
• Data is lacking on actual psychological impact of height restriction due to steroids and interaction of other factors (cushionoid appearance, pubertal delay)
Assessment
o Linear height is not trivial
o Standards need to be laid out and disseminated for measuring height
o National specific growth charts need to be used
o Need to determine how GH is to be measured.
Height data could be added to the current data collection natural history collaboration with Treat NMD and other groups.
If assessments of GH are possible could they be addressed as an add-on to the upcoming Treat NMD steroid trial?
It was generally thought that a retrospective look may have quality issues and may not provide useful information. The participants recommended Dr. Rutter’s data be thoroughly analyzed and may provide a starting point.
Intervention
o GH data need to be assessed both in respect to height gain and strength/function
o Timing of intervention need to be determine
o Concern that this intervention will necessarily be individualized rather than a standardized treatment
o Pilot data may be interesting/informative from Cincinnati cohort already treated
o TACT review of potential for trial (June meeting)
SESSION 2 – PUBERTY
High dose steroids result in delayed or arrested puberty. Cincinnati Children’s has 486 boys in their database. 60 boys ages 13 and older were given pubertal exams and tested for testosterone levels. 16 of these young men were not included in the case study because they were adults and on low or an intermittent dose of steroids. 43/44 of these young men had no evidence of puberty. Their testosterone levels were undetectable. All of the young men had small penises. 15 of the boys have been treated with 1/month injections of testosterone. By adulthood, young men would be on testosterone regimens every two weeks. In some cases AndroGel (topical testosterone) was used.
Young men treated with testosterone have experienced changes related to puberty – increased facial hair, increased size of penis, changes in facial distortion.
Assessment
• Pubertal delay or complete suppression of puberty is seen with prolonged steroid use.
• Testosterone replacement is possible.
• No concerns expressed with testosterone replacement.
• Guidelines are needed to include assessments and timing of interventions.
Intervention
• Testosterone (AndroGel)
SESSION 3 – BONE HEALTH
Published evidence suggests, children with Duchenne have an increased risk of fracture which is exacerbated by chronic steroids use. C. McDonald’s paper suggested that Duchenne boys who do not take steroids have a high incidence of fracture. W. King’s paper noted 32% have vertebral fractures in steroid group and an increased risk (2.6X) of long bone fractures. Bothwell predicted a 75% risk of fracture following 100 months of steroids use.
The effect of steroids and Duchenne on bone are complex. While steroids affect the rate of bone growth and therefore bone mass, immobility adds to the reduction in bone mass. In addition, it is difficult to establish consensus/clear guidance on how to measure bone mineral density and how to interpret results. Boys with Duchenne, even those who do not use steroids, have low bone mineral density and the bone mineral content does not increase normally with age.
Bisphosphonate treatment is indicated when a vertebral fracture is present to reduce acute pain and to preserve bone density in the future. There is no agreement on prophylactic treatment.
UK consensus statement applied across 19 centers recommends DXA scans annually at the start of steroids and Vitamin D levels. The statement includes the recommendation to treat vertebral fractures with IV Bisphosphonate.
Kate Bushby recommends Risedronate 35mg; calcium 500mg. and Vitamin D 400 U. to her patients on daily steroids. Side effects are monitored to include dental prophylactics, urinary calcium/creatine rati, and DXA every 12 months.
Bone health in Duchenne is a challenge. Challenges include:
• Cumulative dose of (at least daily) steroid regimes to have an impact on bone health and can lead to painful vertebral fractures which can limit ambulation.
• Can we optimize steroid regimes to minimize risks while maintaining functional benefit?
• Can we decide on a rational regimen for prophylaxis?
• Does this require Randomized Clinical Trials (RCT)?
• Is it acceptable to provide interim guidance as the burden of steroid treatment in the community increases?
• Bone health is complex, the elements include: density/strength/quality.
• DXA considered gold standard for measuring Becker muscular dystrophy.
• In Duchenne, the increased risk of fracture is 5% per year
• Pediatric position 2007 – only Z score should be considered. Is this sufficient in Duchenne?
Assessment
• Relationship emerging between DXA data and fracture risk in children.
• There is increasing experience of bisphosphonates in children and in the Duchenne population in particular
• Randomized Clinical Trial (RCT) is planned for trial in Australia. Are others needed?
• Need guidelines for assessment and prophylaxis.
• Vitamin D needs to be measured and supplemented.
Interventions
• Calcium, Vitamin D
• Bisphosphonates
SESSION 4 – WEIGHT GAIN
The impact of increased weight in Duchenne includes carbohydrate intolerance, diabetes, heart disease, impaired lung function, decreased mobility, further weight gain, increased osteoporosis, poor self-image, increased caregiver burden, and quality of life for everyone. While it is easy to say ‘calories in, calories out’, the issue is complex. Clinical evaluation on growth must be evaluated. This should be accompanied by dietary evaluation and screening labs (fasting glucose, including HbA1c) and in some cases GTT. Options include altering steroid dose and regimen, improved diet (exercise), and medications. Metformin is an insulin sensitizing agent that improves weight and insulin resistance in patients with diabetes and excessive weight. Recommended dose is 1000-2000mg/day.
In Cincinnati, 15 boys have been treated with Metformin. Most had normal glucoses. ALL had insulin resistance. Metformin was used as an adjunctive treatment in addition to diet. 13/15 boys lost weight with improved self-esteem and quality of life.
Assessment
• Weight gain
• Dietary Evaluation
• Screening blood tests
• Need to establish threshold for GTT
Intervention
• Diet/Education – Consider Weight Watchers or similar
• 75-80% normal intake for ambulant boys
• Non-ambulant 60-75%
• Consider Metformin for those with proven insulin resistance and extreme weight gain.
• Are there straightforward guidelines from other specialties or adult practice?
STOPPING STEROIDS – Steroid Withdrawal
The main effect of glucocortoid is suppression of adrenal glands. This suppression results in feedback to the pituitary and hypothalamus and results in decreased CRH and ACTH). High doses or too much glucocorticoid is associated with cushionoid syndrome and chronic steroid administration results in hypothalamus – pituitary adrenal suppression, which is dose, duration, and mode dependent. Withdrawal from a steroid regimen has to be done in consultation with your physician.
Recommended way to withdraw from steroid:
1. Reduce dose by 25% on a 1-2 wk, basis.
2. When at physiological dose switch to equivalent dose of hydrocortisone 12mg/m2/day.
3. Decrease by 2 ½ mg/wk.
4. Emergency care guidelines in place.
One KEY point is that the circadian rhythm recovers first.
Assessments
• Stress testing after a year of steroids.
• Need more data in this specific condition (antibody response to immunization, stress response).
Interventions
• Emergency guidelines need to be reinforced.
Participants in the meeting:
Tony Hunyh (Endocrinologist, Australia)
Meilan Rutter (Endocrinologist, USA)
Maria Luisa Bianchi (Endocrinologist, Italy)
Peter Hindemarsh (Endocrinologist, UK)
Kate Bushby (Clinical Genetics, Newcastle)
Kevin Flanigan (Neurologist, USA)
Doug Biggar (Pediatrician, Canada)
Brian Tseng (Neurologist, USA)
Diana Escolar (Neurologist, USA)
Larry Markham (Cardiologist, USA)
Chris Condin (Anthropologist, Canada)
Josh Winheld - In memory
Saywatanayo (Shawshank Redemption)
To my friend Josh,
I’m sure heaven is a brighter place today, but our world feels pretty empty. We did not have time to say goodbye. Or time to tell you all of the things that come to mind today or how thankful we were to know you, to have you in our lives, to learn from you, to see you smile.
You had learned all of the lessons life had to teach. You shared your knowledge, spread your joy and extended your hand to all of us. You made our lives better. You made us better.
For the last two years, you participated in the expert panel during PPMD’s annual conference. In your blog, you wrote –“ the main theme of our talk was that life does not end with a wheelchair. We have all been able to accomplish much in our lives, despite being in chairs”. You were living proof that a wheelchair should not be considered an obstacle to success.
Later you blogged “I have no choice except to live to the best of my ability. After all, I could be around for a while and it would be a shame to waste even a second. To quote that noted philosopher, Ferris Bueller, "Life moves pretty fast. If you don't stop and look around once in a while, you could miss it." You inspired us to live today and everyday.
We leaned on you for your insight, for your courage, for your wisdom and for your humor. Just after Scott Sands’ received his pacemaker/defibrillator implant, you wrote “may your heartbeats be regular and your shocks be few”. Josh, you had first hand experience with this device, but your message hits home.
Like you Josh, I love the movie “The Shawshank Redemption”. In the film, Andy Dufresne and Ellis “Red” Redding were prisoners at Shawshank Prison. Andy and Red met while serving time for 1st degree murder. While in prison Andy believed his life would not end in Shawshank prison. He invited Red to be his business partner after serving his time. Red had little hope of freedom. Andy escaped from Shawshank. Sometime later, Red was granted parole.
You were working on your thesis at the time and wrote: “Even when I have the time, my energy often betrays me, thanks to my weak DMD heart and the medications I take to sustain it. After getting shocked 18 times by my internal defibrillator on one very scary night in July, I had to make sure that I did not allow myself to get too stressed out! So I tried to work at a slower pace, taking frequent breaks. It was highly frustrating, but I knew that (like Red, when he found the note Andy left for him) if you had come this far, you could go just a little bit further.
Andy’s letter:
Dear Red, If you are reading this, you have gotten out and if you had come this far, maybe you are willing to come just a little bit further. You remember the name of the town don’t you? (Saywatanayo)
I could use a good man to help me get my project on wheels. I’ll keep an eye out for you and the chessboard ready. Remember Red. Hope is a good thing, maybe the best things and no good thing ever dies. I will be hoping that this letter finds you and finds you well. Your friend, Andy
And on November 9, you added the finishing touches to your masters thesis and submitted it. You were tired and wrote “if only for a moment, I was able recapture some of my old magic, pushing myself every time I wanted to take a break. We'll see what happens, but it sure was nice to visit with my old self and to know he is still within me and I can channel him from time to time! Like Red, you were able to go just a bit further.
And now you are gone.
Josh, I like the words of Leonard Cohen. We are all
“passing through, passing through,
sometimes happy, sometimes blue.
(but very) Glad that we ran into you”
Josh, Hope IS a good thing and no good thing ever dies. If we could photograph HOPE, it would be your smiling face. I am hoping this note reaches you and finds you well. You are loved.
Your friend, Pat
To my friend Josh,
I’m sure heaven is a brighter place today, but our world feels pretty empty. We did not have time to say goodbye. Or time to tell you all of the things that come to mind today or how thankful we were to know you, to have you in our lives, to learn from you, to see you smile.
You had learned all of the lessons life had to teach. You shared your knowledge, spread your joy and extended your hand to all of us. You made our lives better. You made us better.
For the last two years, you participated in the expert panel during PPMD’s annual conference. In your blog, you wrote –“ the main theme of our talk was that life does not end with a wheelchair. We have all been able to accomplish much in our lives, despite being in chairs”. You were living proof that a wheelchair should not be considered an obstacle to success.
Later you blogged “I have no choice except to live to the best of my ability. After all, I could be around for a while and it would be a shame to waste even a second. To quote that noted philosopher, Ferris Bueller, "Life moves pretty fast. If you don't stop and look around once in a while, you could miss it." You inspired us to live today and everyday.
We leaned on you for your insight, for your courage, for your wisdom and for your humor. Just after Scott Sands’ received his pacemaker/defibrillator implant, you wrote “may your heartbeats be regular and your shocks be few”. Josh, you had first hand experience with this device, but your message hits home.
Like you Josh, I love the movie “The Shawshank Redemption”. In the film, Andy Dufresne and Ellis “Red” Redding were prisoners at Shawshank Prison. Andy and Red met while serving time for 1st degree murder. While in prison Andy believed his life would not end in Shawshank prison. He invited Red to be his business partner after serving his time. Red had little hope of freedom. Andy escaped from Shawshank. Sometime later, Red was granted parole.
You were working on your thesis at the time and wrote: “Even when I have the time, my energy often betrays me, thanks to my weak DMD heart and the medications I take to sustain it. After getting shocked 18 times by my internal defibrillator on one very scary night in July, I had to make sure that I did not allow myself to get too stressed out! So I tried to work at a slower pace, taking frequent breaks. It was highly frustrating, but I knew that (like Red, when he found the note Andy left for him) if you had come this far, you could go just a little bit further.
Andy’s letter:
Dear Red, If you are reading this, you have gotten out and if you had come this far, maybe you are willing to come just a little bit further. You remember the name of the town don’t you? (Saywatanayo)
I could use a good man to help me get my project on wheels. I’ll keep an eye out for you and the chessboard ready. Remember Red. Hope is a good thing, maybe the best things and no good thing ever dies. I will be hoping that this letter finds you and finds you well. Your friend, Andy
And on November 9, you added the finishing touches to your masters thesis and submitted it. You were tired and wrote “if only for a moment, I was able recapture some of my old magic, pushing myself every time I wanted to take a break. We'll see what happens, but it sure was nice to visit with my old self and to know he is still within me and I can channel him from time to time! Like Red, you were able to go just a bit further.
And now you are gone.
Josh, I like the words of Leonard Cohen. We are all
“passing through, passing through,
sometimes happy, sometimes blue.
(but very) Glad that we ran into you”
Josh, Hope IS a good thing and no good thing ever dies. If we could photograph HOPE, it would be your smiling face. I am hoping this note reaches you and finds you well. You are loved.
Your friend, Pat
A moment for thanks
We spend most of our lives in running shoes. This past year in particular, there were added worries, and it felt like we had to run stronger and faster, often without taking a moment to catch our breath.
On Thanksgiving, it is important to loosen those laces, put the shoes in a corner, and take a moment to bow our heads and give thanks.
I am thankful…
•…for amazing advances in research. Our End Duchenne Grant Award Program invested almost $1 million in research, leveraging more than $18 million from the NIH. We hope to add more clinical trial candidates for promising compounds in the next six months.
•…that "Care Considerations in Duchenne" will be published in the January and February issues of Lancet which defines optimal care for Duchenne. It will empower physicians and parents and open the door for children worldwide to access optimal care.
•…that collaborations have expanded and that major pharmaceutical companies have joined our fight to End Duchenne.
•…to the Duchenne community, for your relentless efforts to have the voices of our sons heard.
•…for the continued "can do" spirit of every family, clinician, and researcher, and the partnerships with organizations that are working together for the benefit of so many young men with Duchenne.
While I always have my running shoes on for Duchenne, this year I found myself in another race. My husband Tom was diagnosed with colon cancer.
Like the word Duchenne, the word cancer entered our home uninvited. After losing Chris and Patrick, we sort of figured that we had a "get out of jail free" card for the rest of our lives. It was devastating, but we found a world of support and prayers from family, friends, and this wonderful, supportive community. And I'm happy to say that Tom is in treatment and doing well.
Although I do not say it nearly often enough, I am most grateful for the support of family and friends. In my life, you make all the difference in the world.
Please tell me what you're thankful for. Post your thoughts below. Because you are a part of the PPMD family, we would like to share in your challenges and celebrations.
Happy Thanksgiving. And again, I can't thank you all enough for the amazing support you've shown all year long.
On Thanksgiving, it is important to loosen those laces, put the shoes in a corner, and take a moment to bow our heads and give thanks.
I am thankful…
•…for amazing advances in research. Our End Duchenne Grant Award Program invested almost $1 million in research, leveraging more than $18 million from the NIH. We hope to add more clinical trial candidates for promising compounds in the next six months.
•…that "Care Considerations in Duchenne" will be published in the January and February issues of Lancet which defines optimal care for Duchenne. It will empower physicians and parents and open the door for children worldwide to access optimal care.
•…that collaborations have expanded and that major pharmaceutical companies have joined our fight to End Duchenne.
•…to the Duchenne community, for your relentless efforts to have the voices of our sons heard.
•…for the continued "can do" spirit of every family, clinician, and researcher, and the partnerships with organizations that are working together for the benefit of so many young men with Duchenne.
While I always have my running shoes on for Duchenne, this year I found myself in another race. My husband Tom was diagnosed with colon cancer.
Like the word Duchenne, the word cancer entered our home uninvited. After losing Chris and Patrick, we sort of figured that we had a "get out of jail free" card for the rest of our lives. It was devastating, but we found a world of support and prayers from family, friends, and this wonderful, supportive community. And I'm happy to say that Tom is in treatment and doing well.
Although I do not say it nearly often enough, I am most grateful for the support of family and friends. In my life, you make all the difference in the world.
Please tell me what you're thankful for. Post your thoughts below. Because you are a part of the PPMD family, we would like to share in your challenges and celebrations.
Happy Thanksgiving. And again, I can't thank you all enough for the amazing support you've shown all year long.
HOPE – finding the Therapeutic Dose
It’s not easy. The word Duchenne enters our lives. We search the internet, seek out expertise, connect with researchers, clinicians, industry, other families, set up our internet tools (Google alerts, RSS feeds, list-serves, pubmed search criteria, industry alerts, etc) and live each day hoping to see our ‘in-box’ overflowing with news, with HOPE.
On any given day, you reassure yourself that your son is young, may have a certain mutation, may have a certain degree of muscle function, may have what it takes to participate in a promising clinical trial. You connect with experts in the field as an insurance policy for today and tomorrow, to protect and preserve strength. You connect with others who are in the ‘know,’ who may recommend supplements, approved drugs that they believe have some degree of effect. This may be based on a study in the mdx mouse, a clinical trial for another condition and/or a guess, based on knowledge of the downstream pathology of Duchenne. It may be a response to the question “if this was your son, what would you do?” posed to a physician, researcher or a parent with experience or knowledge and/or coerce your doctor to write a script for a drug on the basis of mdx data and use in other populations. How many times have we all said "It won’t hurt and may help, so let’s try.”
On another day, you may find yourself dragging around because, for some reason, it hits you that everything takes time, too much time and you wonder, “Will it be in time for my son?” Or you walk around the entire day praying that your son walks or that your son continues to move his arms, continues to breathe without ventilation, continues to breathe, continues to have a healthy heart.
On another day, your son falls, or it’s the day of the school IEP, or he is no longer walking or someone says the wrong thing or you read about a trial design that involves only ambulatory boys and you find it hard to talk, hard to hold back tears. Or your son has a fever and your heart stops in its tracks, worried about cold, flu, pneumonia.
On another day, a random person in the media will use words like 'breakthrough' or ‘cure’ or ‘promising treatment’ and you wonder…Is it real?
Hope is a good thing, but it is often impossible to find the right balance, to take in the overwhelming amount of information and make sense of it… make sense of it for your life and what it means for your son.
As a community, we have a great deal of experience with dose escalation. HOPE - Trials, each of us working hard to find our own therapeutic dose.
On any given day, you reassure yourself that your son is young, may have a certain mutation, may have a certain degree of muscle function, may have what it takes to participate in a promising clinical trial. You connect with experts in the field as an insurance policy for today and tomorrow, to protect and preserve strength. You connect with others who are in the ‘know,’ who may recommend supplements, approved drugs that they believe have some degree of effect. This may be based on a study in the mdx mouse, a clinical trial for another condition and/or a guess, based on knowledge of the downstream pathology of Duchenne. It may be a response to the question “if this was your son, what would you do?” posed to a physician, researcher or a parent with experience or knowledge and/or coerce your doctor to write a script for a drug on the basis of mdx data and use in other populations. How many times have we all said "It won’t hurt and may help, so let’s try.”
On another day, you may find yourself dragging around because, for some reason, it hits you that everything takes time, too much time and you wonder, “Will it be in time for my son?” Or you walk around the entire day praying that your son walks or that your son continues to move his arms, continues to breathe without ventilation, continues to breathe, continues to have a healthy heart.
On another day, your son falls, or it’s the day of the school IEP, or he is no longer walking or someone says the wrong thing or you read about a trial design that involves only ambulatory boys and you find it hard to talk, hard to hold back tears. Or your son has a fever and your heart stops in its tracks, worried about cold, flu, pneumonia.
On another day, a random person in the media will use words like 'breakthrough' or ‘cure’ or ‘promising treatment’ and you wonder…Is it real?
Hope is a good thing, but it is often impossible to find the right balance, to take in the overwhelming amount of information and make sense of it… make sense of it for your life and what it means for your son.
As a community, we have a great deal of experience with dose escalation. HOPE - Trials, each of us working hard to find our own therapeutic dose.
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