Connecting with the World:

Transcription

1

2 Connecting with the World: Updates and Insights from Multicenter Study of Rare Disease in the Adult Airway November 3, 2016 Alexander Gelbard MD Vanderbilt University School of Medicine 4th Annual Contemporary Management of Aerodigestive Disease in Children

3 NoAAC Funded by PCORI Grant #: PI(s): Alexander Gelbard MD, David Francis MD

4 Outline Knowledge gaps in LTS Basic Principles of Improving Care of Rare disease Application of these Rare disease principles to LTS Insights from ongoing prospective trial in adult isgs.

5 Laryngotracheal Stenosis (LTS) Vocal Folds Subglottis Trachea Vocal Folds

6 Adult LTS Etiologies Idiopathic Autoimmune Iatrogenic (post intubation)

7 Adult LTS Etiologies Idiopathic Autoimmune Iatrogenic (post intubation)

8 Normal ( isgs PFTs Exp. Normal isgs Insp.

9 Incidence of Idiopathic Subglottic Stenosis: 1 in 200,000

10 Nor is there any better way to advance the proper practice of medicine than by the careful investigation of cases of rarer forms of disease. Dr. William Harvey, Fellow of the Royal College of Physicians Physician to King James I.

11 How do you cure a rare disease?

12 How do you cure a rare disease? First you have to characterize the natural history and clinical epidemiology.

13 How do you cure a rare disease? First you have to characterize the natural history and clinical epidemiology. Natural history studies are essential to: Identify biomarkers for monitoring treatment response Validate outcome measures for monitoring treatment response Create large patient cohorts Collect biospecimens Create centers of expertise Develop hypothesis for translational research

14 How do you cure a rare disease? First you have to characterize the natural history and clinical epidemiology. Natural history studies are essential to: Identify biomarkers for monitoring treatment response Validate outcome measures for monitoring treatment response Create large patient cohorts Collect biospecimens Create centers of expertise Develop hypothesis for translational research

15 Natural History Studies have defined your rare disease:

16 Natural History Studies have defined your rare disease: Now how do you cure it?

17 How do you cure a rare disease?

18 Translational Science in Rare Disease (1780s)

19 How do you cure a rare disease? 1. Pioneer a new surgery or a better medicine Juvenile Diabetes discovery of insulin

20 How do you cure a rare disease? 1. Pioneer a new surgery or a better medicine Juvenile Diabetes discovery of insulin 2. Uncover the molecular pathway responsible, then block it. Chronic Myeloid leukemia (BCR/ABL + CML) Gleevac

21 How do you cure a rare disease? 1. Pioneer a new surgery or a better medicine Juvenile Diabetes discovery of insulin 2. Uncover the molecular pathway responsible, then block it. Chronic Myeloid leukemia (BCR/ABL + CML) Gleevac 3. Uncover the exposure that creates the disease, and stop it. Cervical Cancer HPV vaccine

22 How do you cure a rare disease? 1. Pioneer a new surgery or a better medicine Juvenile Diabetes discovery of insulin 2. Uncover the molecular pathway responsible, then block it. Chronic Myeloid leukemia (BCR/ABL + CML) Gleevac 3. Uncover the exposure that creates the disease, and stop it. Cervical Cancer HPV vaccine 4. Establish a large network of patients & watch response to therapy. Wilms tumor

23 How do you cure a rare disease? 1. Pioneer a new surgery or a better medicine Juvenile Diabetes discovery of insulin 2. Uncover the molecular pathway responsible, then block it. Chronic Myeloid leukemia (BCR/ABL + CML) Gleevac 3. Uncover the exposure that creates the disease, and stop it. Cervical Cancer HPV vaccine 4. Establish a large network of patients & watch response to therapy. Wilms tumor

24 Childhood Cancers 30% - Leukemia 25% - Central nervous system tumors 7% - Lymphoma (Hodgkin (3%) and non-hodgkin (5%)) 6% - Neuroblastoma 5% - Wilms tumor 3% - Rhabdomyosarcoma 3% - Bone cancer (osteosarcoma and Ewing sarcoma) 2% - Retinoblastoma

25 Childhood Cancers 30% - Leukemia 25% - Central nervous system tumors 7% - Lymphoma (Hodgkin (3%) and non-hodgkin (5%)) 6% - Neuroblastoma 5% - Wilms tumor 3% - Rhabdomyosarcoma 3% - Bone cancer (osteosarcoma and Ewing sarcoma) 2% - Retinoblastoma

26 Wilms Tumor

27 Wilms Tumor 100 Overall Survival (%) Year Surgery XRT Chemo

28 Wilms Tumor 100 Overall Survival (%) Surgery XRT Chemo NWTS

29 Wilms Tumor 100 Overall Survival (%) Surgery XRT Chemo NWTS

30 How do you cure a rare disease? Just by working together and comparing the treatments already in practice, the survival for Wilms tumor jumped from 40% to 90%. This happened along with reductions in treatment toxicity and long term side-effects.

31 Translational Science in Rare Disease (2016) North American Airway Collaborative (NoAAC)

32 NoAAC RP-01 Study; Patient Characteristics (n=479) % Female % Caucasian Num. of Patients Institution Gelbard et al. Disease Homogeneity and Treatment Heterogeneity in Idiopathic Subglottic Stenosis. NoAAC RP-01 study. Laryngoscope 2015

33 Variation in Treatment Approach (n = 10 centers) Endo (% cases) Open (% cases) Study Location

34 Treatment Outcomes (n = 10 centers)

35 Open Treatment Outcomes

36 Open Treatment Outcomes

37 Open Treatment Outcomes

38 isgs Endoscopic Treatment Outcomes

39 isgs Endoscopic Treatment Outcomes

40 isgs Endoscopic Treatment Outcomes

41 isgs Endoscopic Treatment Outcomes

42 NoAAC RP-01: Lessons Learned isgs is disease of adult Caucasian women Disease is restricted to a defined anatomic location in the subglottis Despite similar patient characteristics, they are treated differently at unique institutions.

43 North American Airway Collaborative (NoAAC) Treatment Alternatives in Adult Rare Disease; Assessment of Options in Idiopathic Subglottic Stenosis NoAAC PR02 Study

44 NoAAC PR-02 Study Prospective Observational Pragmatic Trial in isgs Comparing 3 major treatment strategies Dilation Resection with Adjuvant medications Cricotracheal Resection 1. How well the most commonly used treatments in isgs work? 2. What quality-of-life trade-offs are associated with each approach.

45 NoAAC PR-02 Study Prospective Observational Pragmatic Trial in isgs Comparing 3 major treatment strategies Dilation Resection with Adjuvant medications Cricotracheal Resection 1. How well the most commonly used treatments in isgs work? 1. How well the most commonly used treatments in isgs 2. What quality-of-life trade-offs are associated with each approach. work? 2. What quality-of-life trade-offs are associated with each approach.

46 Dyspnea

47 350 pt8 PF Dyspnea

48 350 pt8 PF 450 pt222 PF Dyspnea

49 350 pt8 PF 450 pt222 PF pt8 steps Dyspnea

50 350 pt8 PF 450 pt222 PF pt8 steps pt222 steps Dyspnea

51 NoAAC PR02 Study Enrollment 600 Enrolled Patients Study Duration (Weeks)

52 NoAAC PR02 Study Enrollment patients Enrolled Patients Study Duration (Weeks)

53 NoAAC PR02 Study Enrollment Enrolled Patients Self-enrolled Refering Institution

54 NoAAC PR02 Study Enrollment 50 Enrolled Patients Refering Institution

55 NoAAC PR02 Patient Residence

56 NoAAC PR02 Patient Residence

57 NoAAC PR02 Patient Residence Where Patients Live Where Patients Receive Care

58 NoAAC PR02 Patient Demographics Male Female Enrolled Patients

59 NoAAC PR02 Patient Demographics Male Female Enrolled Patients

60 NoAAC PR02 Patient Demographics Northern European Unknown NorthernEuropean & NativeAmerican NorthernEuropean & SouthernEuropean EasternEuropean Native American Southern European Oceanian Oceanian & NorthernEuropean Ashkenaz Middle Eastern South African Southeast Asian Male Female Enrolled Patients

61 NoAAC PR02 Patient Demographics Some college High school Married Divorced Never married Domestic partnership Widowed Separated College Graduate school Less than high school graduate Enrolled Patients Enrolled Patients

62 NoAAC PR02 Enrollment Goal over next 10 months 1500 Enrolled Patients Study Duration (Weeks)

63 NoAAC PR02 Enrollment Goal over next 10 months 1500 Enrolled Patients Study Duration (Weeks)

64 Thanks Clinicians: Dr. David Francis (PCORI co-pi) Dr. Christopher Wootten (PCORI Co-I) Dr. C. Gaeyln Garrett Dr. James Netterville Lab: Dr. Bernard Rousseau Dr. Masanobu Mizuta Hongmei Wu Collaborators: Dr. Timothy Blackwell Dr. Wonder Drake Dr. Charles Stratton Dr. Dawn Newcomb Dr. Jen Gaddy NoAAC Co-Investigators: Mr. Guri Sandhu Dr. Alexander Hillel NoAAC Investigators