# Presentation: 758861

## NDA 21-514  DAYTRANATM (methylphenidate transdermal system)Psychopharmacologic Drugs Advisory Committee

- Douglas Hay, PhD Senior Vice President, Global Regulatory Affairs
- Shire Pharmaceuticals

*co-developed by* Noven Pharmaceuticals, Inc.Shire Pharmaceuticals

## Proposed Indication for Methylphenidate Transdermal System (MTS)

- DAYTRANATM (methylphenidate transdermal system) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD)

## External Consultants

- Stephen V. Faraone, PhD
- Professor of Psychiatry and Director Child and Adolescent Psychiatric ResearchSUNY, Upstate Medical University, Syracuse*Drug Effects on Growth in ADHD*
- Marc Lerner, MD
- Clinical Professor of PediatricsUniversity of California, Irvine*Developmental Pediatrics and ADHD*
- Judith Owens, MD, MPH
- Associate Professor of PediatricsBrown University School of Medicine, Providence, RI*Sleep Disorders in ADHD*
- Sharon Wigal, PhD
- Associate Clinical Professor of Pediatrics University of California, Irvine*Clinical Trials in ADHD*

## External Consultants

- David Heal, PhD, DSc
- Director RenaSci Consultancy Ltd, UK *Methylphenidate Pharmacology*
- Jack Henningfield, PhD
- Adjunct Professor, Behavioral BiologyThe Johns Hopkins University School of Medicine
- 	Vice President, Pinney Associates, Bethesda, MD*Risk Management*

## Agenda

- Introduction
- ADHD: Current Treatment
-  Marc Lerner, MD
- 	 University of California, Irvine
- Clinical Efficacy of MTS in the Treatment of ADHD
- Liza Squires, MDSr. Director, Clinical Research, Shire Pharmaceuticals
- Safety and Tolerability of MTS in Children with ADHD
- Raymond Pratt, MD Vice President,  Global Clinical Medicine, Shire Pharm.
- Clinical Perspective of MTS Treatment of ADHD
- Sharon Wigal, PhD University of California, Irvine
- Overall Benefit/Risk of MTS in the Treatment of ADHD
- Raymond Pratt, MD

## Rationale for the Development of Transdermal Methylphenidate

- Alternative for patients with difficulty swallowing pills
- Caregivers indicate ~15% of children with ADHD have “extreme” or “high difficulty” in swallowing pills
- Avoids any food effect
- Concern with many oral ADHD medications
- Opportunity to visibly monitor compliance
- Sustained treatment without need for supplemental therapy
- Flexible period of treatment in children requiring an altered regimen

## Methylphenidate Transdermal System

**Backing**

**Drug/Adhesive ****Mix**

**Release Liner**

**Methylphenidate Transdermal System**

- Backing is a vinyl acetate laminate film
- Inner polyester release liner  removed before use
- DOT MatrixTM Technology
- concentrated drug-in-microacrylic cells
- acrylic cells homogenously dispersed in pressure-sensitive silicone

## Methylphenidate Transdermal System

- Thin and transparent
- Effective drug delivery over a small patch area
- No need for irritating enhancers
- Excellent adhesion

## Methylphenidate Transdermal Patch Current Dose Strengths

| Dose (mg) delivered 
over 9-h wear time | Patch Surface Area |
| --- | --- |
| 10 mg  (1.1 mg/h†  x 9 h) | 12.5 cm2 |
| 16 mg  (1.8 mg/h† x 9 h) | 18.75 cm2 |
| 20 mg  (2.2 mg/h† x 9 h) | 25 cm2 |
| 27 mg  (3.0 mg/h† x 9 h) | 37.5 cm2 |
| Methylphenidate doses delivered by the MTS patch are comparable to other sustained-release methylphenidate-based products on the market |  |

- †Nominal delivery rate per hour in pediatric subjects aged 6-12

**Methylphenidate Transdermal**** Patch Current Dose Strengths**

## MTSRegulatory / Development History 

- NDA 21-514 submitted by Noven June 2002
- 12-*hour* wear time
- FDA Action Letter April 2003
- acknowledged efficacy of MTS
- identified incidence of insomnia, anorexia, and weight loss as unacceptable
- recommended consideration of shorter duration of wear time to potentially mitigate these, as well as dermal effects
- Noven and Shire signed collaborative agreement in 2003
- Discussions with FDA regarding subsequent clinical program;  9-*hour* wear time
- NDA resubmission on June 28, 2005

## Noven / ShireMTS Clinical Development Program 

**Noven / Shire****MTS Clinical Development Program **

- Pharmacokinetic (PK) and Biopharmaceutic Studies
- 8 studies in volunteers (n=407)
- PK, dose proportionality, skin irritation and sensitization, and abuse potential
- 4 studies in pediatric patients (n=97)
- application site, patch size, and wear time on PK
- Initial Dose-ranging Studies (n=24)
- 2 studies with an early formulation
- classroom and laboratory settings

## Noven / ShireMTS Clinical Development Program

| Study Type  | Study Description  | Study Number  | Number of Subjects |
| --- | --- | --- | --- |
| Phase II, Controlled, Short-Term Studies  | Placebo-controlled, crossover safety and efficacy studies in a summer treatment program setting  | N17-009
N17-015  | 63  |
|  | Placebo-controlled, multi-dose, crossover safety and efficacy study in a classroom setting; 9 hour | SPD485-201 | 93 |
| Phase III, Controlled, Short-Term Studies | Placebo-  and active-controlled, multi-dose, randomized, safety and efficacy studies; 12 hour | N17-010 
N17-018  | 210 
211  |
|  | Placebo-  and active-controlled, multi-dose, randomized, safety and efficacy study; 9 hour | SPD485-302 | 282  |
| Uncontrolled, Long-Term Studies | Open-label, long-term safety studies; 12 hour | N17-011 
N17-013 
N17-021  | 118 
20 
191 |
|  | Open-label, long-term safety study; 9 hour | SPD485-303 | 289  |

**Noven / Shire****MTS Clinical Development Program**

## ADHD: Current Treatment

- Marc Lerner, MDClinical Professor of Pediatrics
- University of California, Irvine

## Prevalence and Public Health Impact of ADHD

- ADHD affects 3-5% of all school-age children1
- Recent data suggests rates up to 7.5% in school-aged children2
- Diagnosed in boys at rates up to 4 times more than in girls3,4
- ADHD accounts for up to 50% of mental health referrals for children5
- ADHD often persists throughout childhood into adolescence and adulthood6,7,8

## Risks Associated with ADHD

- Academic1,2,3,4,5,6
- Poor academic performance
- Higher drop-out rate
- Suspension / expulsion
- Social8,9
- Interaction problems with teachers, peers and parents
- Adult, more often separated, divorced, or unmarried
- Work6,7
- More frequent job changes – quit, fired
- Lower status jobs
- More often unemployed
- Personal10
- Co-morbidity:  ODD, Anxiety, Depression

## Pharmacological Treatment for Children with ADHD

- Clinicians should recommend pharmacotherapy to improve target outcomes in children with ADHD2
- Stimulant medication is a first-line treatment for ADHD1
- Methylphenidate (MPH) reduces core symptoms of ADHD3
- Any individual stimulant effective in ~70% of ADHD patients
- Many who fail to respond to one may respond to another3,4
- Stimulants generally safe and well tolerated4
- Therapeutic goal for stimulants in ADHD is to provide optimal efficacy with manageable side effects

## References

- 14.1	Jensen PS. Ritalin: Theory and Practice, 2nd ed. Larchmont, NY: Mary Ann Liebert, Inc.; 1999:1-3
- 14.2	Barbaresi WJ, Katusic SK, Colligan RC, Pankratz VS, et al. How common is attention-deficit/hyperactivity disorder? Incidence in a population-based birth cohort in Rochester, Minn. Arch Pediatr Adolesc Med. 2002 Mar;156(3):217-24
- 14.3	US Department of Health and Human Services, 1999
- 14.4	Scott-Levin Inc., Physician Drug and Diagnosis Audit (PDDA), 2001
- 14.5	The MTA Cooperative Group, A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999 Dec;56(12):1073-86
- 14.6	Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M. Adult psychiatric status of hyperactive boys grown up. Am J Psychiatry. 1998 Apr;155(4):493-8
- 14.7	Barkley RA, Fischer M, Edelbrock CS, Smallish L. The adolescent outcome of hyperactive children diagnosed by research criteria: I. An 8-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry. 1990 Jul;29(4):546-57
- 14.8	Gittelman R, Mannuzza S, Shenker R, Bonagura N. Hyperactive boys almost grown up. I. Psychiatric status. Arch Gen Psychiatry. 1985 Oct;42(10):937-47
- 15.1	Barkley RA. Major life activity and health outcomes associated with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002;63 Suppl 12:10-5.
- 15.2	Fischer M, Barkley RA, Edelbrock CS, Smallish L. The adolescent outcome of hyperactive children diagnosed by research criteria: II. Academic, attentional, and neuropsychological status. J Consult Clin Psychol. 1990 Oct;58(5):580-8
- 15.3	Hechtman L, Weiss G. Long-term outcome of hyperactive children. Am J Orthopsychiatry. 1983 Jul;53(3):532-41
- 15.4	Faraone SV, Biederman J, Lehman BK, et al. Intellectual performance and school failure in children with attention deficit hyperactivity disorder and in their siblings. J Abnorm Psychol. 1993 Nov;102(4):616-23
- 15.5	Biederman J, Monuteaux MC, Doyle AE, et al. Impact of executive function deficits and attention-deficit/hyperactivity disorder (ADHD) on academic outcomes in children. J Consult Clin Psychol. 2004 Oct;72(5):757-66
- 15.6	Wilens TE, Dodson WA clinical perspective of attention-deficit/hyperactivity disorder into adulthood. J Clin Psychiatry. 2004 Oct;65(10):1301-13
- 15.7	Barkley RA, Fischer M, Smallish L, et alThe persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol. 2002 May;111(2):279-89
- 15.8	Barkley RA, Fischer M, Smallish L, et al. Young adult follow-up of hyperactive children: antisocial activities and drug use. J Child Psychol Psychiatry. 2004 Feb;45(2):195-211
- 15.9	Eakin L, Minde K. Hechtman L. The marital and family functioning of adults with ADHD and their spouses. J Atten Disord. 2004 Aug;8(1):1-10
- 15.10	Biederman J. Impact of comorbidity in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2004;65 Suppl 3:3-7
- 16.1	American Academy of Pediatrics. Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001 Oct;108(4):1033-44
- 16.2	Greenhill LL, Pliszka S, Dulcan MK, Bernet W, et al; American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002 Feb;41(2 Suppl):26S-49S
- 16.3	Spencer TJ, Biederman J, Harding M, O'Donnell D, et al. Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays? J Am Acad Child Adolesc Psychiatry. 1996 Nov;35(11):1460-9
- 16.4	AACAP. Managing ADHD. Version 1.1. Baltimore, MD: International Guidance Center; 2003; Guidelines Pocket Card

## AAP Treatment Guidelines for ADHDPEDIATRICS Vol. 108 No. 4 October 2001, pp. 1033-1044

- Stimulants are generally considered safe medications, with few contraindications to their use
- Side effects occur early in treatment and tend to be mild and short-lived
- The most common side effects are decreased appetite, stomachache or headache, delayed sleep onset, jitteriness, or social withdrawal
- Most side effects can be successfully managed through adjustments of dosage or schedule

## AAP Treatment Guidelines for ADHDPEDIATRICS Vol. 108 No. 4 October 2001, pp. 1033-1044

- Children who fail to show positive effects or who experience intolerable side effects on one stimulant medication should be tried on another
- Children who fail 2 stimulant medications can be tried on a third type or formulation of stimulant medication
- 15% to 30% of children experience motor tics, most of which are transient, while on stimulant medications
- The presence of tics before or during medical management of ADHD is not an absolute contraindication to the use of stimulant medications

## Gaps with Available ADHD Treatments

- Provide clinicians with greater flexibility for ADHD treatment
- Provide families with the opportunity to individualize the child’s treatment to meet the needs of the day
- Options to support the child’s functioning early in the day
- Ability to shorten PM medication impact
- Reduction in multiple prescriptions & co-pays

## “Physicians should be alert for problems with adherence”

- Hippocrates, 200 B.C.

## Issues Related to Treatment Compliance in Children with ADHD

- Doesn’t like the taste
- Doesn’t like taking medications
- Refuses to take the medication
- Gags when taking medication
- Parent gives up due to stress

## Conclusions

- ADHD is a significant, impairing disorder with potential long-term implications
- MPH is a first-line treatment for ADHD
- Some patients respond preferentially to one ADHD treatment over another, AND
- Different treatments offer different advantages
***There is a group of patients that is not receiving optimal therapy******Families need additional therapeutic options***

## Clinical Efficacy of MTS in Children with ADHD

- Liza Squires, MDSenior Director, Global Clinical Medicine
- Shire Pharmaceuticals

## MTS Clinical Development Program Efficacy Objectives

- Establish efficacy with a 9-hour wear time
- Study 201: Laboratory Classroom Study
- Onset and duration
- Study 302: Outpatient Study
- Efficacy in an outpatient setting

## Study 101

- Identify clinically optimal wear time based upon PK profile
- Four arm, single-dose, crossover, PK study
- MTS 25cm2, 6-, 8-, and 10-hour patch wear time and Concerta 36 mg
- 24 children with ADHD age 6-12 years

## Study 101 Plasma Concentration of d-MPH

- MTS06, MTS08 and MTS10 represent wear times before patch removal at 6, 8 and 10 hours, respectively

**MTS 25cm****2  ****(6 hours)**

**MTS 25cm****2  ****(8 hours)**

**MTS 25cm****2  ****(10 hours)**

**Concerta****® ****36 mg**

**0**

**0**

**5**

**10**

**15**

**20**

**25**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**Hour**

***d*****-MPH (ng/mL)**

**Study 101**** ****Plasma Concentration of *****d*****-MPH**

## Study 201MTS Laboratory Classroom Study

- Assess efficacy and time course of treatment effect, tolerability and safety of MTS
- SKAMP Deportment scale (SKAMP-D) scores
- PERMP (Math Productivity) Scores
- Multiple time points during 2 classroom days
- Double-blind, multi-center, placebo-controlled, crossover design laboratory classroom study
- Pediatric patients age 6-12 years diagnosed with ADHD by DSM-IV-TR criteria

## Study 201 Design

**Screening**

**Baseline**

**Randomization ****Practice classroom**

**Follow-up or open label study**

**10 mg* (12.5 cm****2****)**

**16 mg* (18.75 cm****2 ****)**

**20 mg* (25 cm****2 ****)**

**27 mg* (37.5 cm****2 ****) **

**1 Wk**

**Randomization at Week 5**

**     ****MTS**

**     ****MTS**

**1 Wk**

**     ****PTS**

**     ****PTS**

**Laboratory Classroom**

## Laboratory Classroom StudyDaily Schedule

- 6:15	Arrival, Pre-dose Evaluation
- 7:00	Class 0, PERMP, SKAMP
- 7:30	MTS Dosing
- 7:40	Breakfast / Free-time
- 9:15	Vital signs / Bloods
- 9:30	Class 1, PERMP, SKAMP
- 10:00	Snack
- 10:15	Vital signs / Bloods
- 10:30	Class 2, PERMP, SKAMP
- 11:00	Free-time / Bloods
- 12:00	Class 3, PERMP, SKAMP
- 12:30	Lunch / AE Assessment
- 13:15	Vital signs / Bloods
- 13:30	Class 4, PERMP, SKAMP

- 14:00	Free-time / Physical / ECG
- 14:45	Vital signs / Bloods
- 15:00	Class 5, PERMP, SKAMP
- 15:30	Snack / Free-time / AE Assessment
- 16:15	Vital signs / Bloods / MTS Removal
- 16:30	Class 6, PERMP, SKAMP
- 17:00	Free-time
- 17:45	Vital signs / Bloods
- 18:00	Class 7, PERMP, SKAMP
- 18:30	Dinner / Free-time / AE Assessment
- 19:15	Vital signs / Bloods
- 19:30	Class 8, PERMP, SKAMP
- 20:00	Dismissal

## Study 201 Primary AnalysisSKAMP Deportment Score (0-9 Hours)

|  | MTS | PTS |
| --- | --- | --- |
|  | N=79 | N=79 |
| Mean (SD) | 3.2  3.6 | 8.0  6.3 |
| Median | 2.2 | 7.3 |
| Range | 0 to 17 | 0 to 29 |
| LS Mean (SE) | 3.2  0.6 | 8.0  0.6 |
| Difference and 95% CI of LS Mean (MTS-PTS) | -4.8
95% CI -5.9 to -3.6 |  |
| p-value | <0.0001 |  |

## Study 201 SKAMP-D Onset & Duration

## Study 201 PERMP Number Attempted & Correct

## Study 201Secondary Efficacy Endpoints

| Scale | p-value | MTS-PTS Difference [95% CI] |
| --- | --- | --- |
| SKAMP (Total) | p<0.0001 | -8.5 
[-10.2 to -6.8] |
| ADHD-RS-IV (Total) | p<0.0001 | -16.5 
[-19.8 to -13.1] |
| CPRS (Total) | p<0.0001 | -15.1 
[-20.5 to -9.7] |
| PGA | p<0.0001 | Improved (1 or 2) 
65-76% |
| CGI | p<0.0001 | Improved (1 or 2) 
78-80% |

## Study 201Efficacy Summary

- Overall efficacy of MTS in reducing ADHD symptoms apparent to trained observers, clinicians and parents
- Statistically significant improvement in all primary and secondary efficacy endpoints
- 9-hour target wear time
- Onset of effect within 2 hours of application
- Duration of effect through 12 hours

## Study 302 Design

- Evaluate the safety and efficacy of methylphenidate transdermal system (MTS) compared to placebo with reference to Concerta®
- A phase III, randomized, double-blind, multi-center, parallel-group, placebo-controlled, dose-optimization study
- 38 study centers in the US – 274 subjects
- Pediatric patients age 6-12 years with ADHD by DSM-IV-TR criteria

## Study 302 Design

## Study 302  Clinical Outcome Measures

- Primary Outcome
- Clinician-rated ADHD-RS-IV
- Secondary Outcomes
- Conners’ Teacher Rating Scale Revised SF (CTRS-R)
- Conners’ Parent Rating Scale Revised SF (CPRS-R)
- Clinical Global Impressions (CGI-I)
- Parent Global Assessment (PGA)

## Study 302Subject Demographics – ITT

| Characteristic | MTSN=96  | Concerta® N=89 | Placebo
N=85 | OverallN=270 |
| --- | --- | --- | --- | --- |
| Mean age in yrs (±SD) | 8.8(1.91) | 8.8(1.93) | 8.5(1.90) | 8.7(1.91) |
| Sex Male (%) | 60 | 66 | 74 | 67 |
| Race (%)
	Caucasian	African-American  	Asian	Other | 
791227 | 
801407 | 
731908 | 
771417 |

## Study 302: ADHD-RS-IV Change from Baseline to Endpoint

|  | MTSN=96 | Concerta®N=89 | PlaceboN=85 |
| --- | --- | --- | --- |
| ADHD-RS-IVBaseline Score | 43.07.5 | 43.86.7 | 41.97.4 |
|  | Change From Baseline (LOCF) |  |  |
| LS Mean  SE | -24.21.5 | -21.61.5 | -10.31.5 |
| Difference Active – Placebo[95% CI] | -13.9[-18.06 to -9.7] | -11.3[-15.6 to -7.06] |  |
|  | p<0.0001 | p<0.0001†  |  |
|  |  |  |  |

- †Reference only not a primary comparison

## Study 302: ADHD-RS-IV Change from Baseline to Endpoint

- *p<0.05 MTS vs placebo

## Study 302Secondary Efficacy Endpoints

|  |  | Active – Placebo Difference [95% CI] |  |
| --- | --- | --- | --- |
|  | P-value†  | MTS | Concerta® |
| Teacher (CTRS-R) Total | <0.0001 | -10.2 [-15.0 to -5.4] | -12.4 [-17.4 to -7.5] |
|     ADHD Index | <0.0001 | -5.8 [-8.4 to -3.2] | -7.2 [-9.8 to -4.6] |
|     Oppositional | 0.0345 | -0.8 [-1.5 to -0.1] | -1.0 [-1.7 to -0.2] |
|     Hyperactivity | <0.0001 | -2.7 [-4.2 to -1.3] | -3.4 [-4.8 to -1.9] |
|     Cognitive problems | 0.0040 | -1.4 [-2.4 to -0.5] | -1.8 [-2.8 to -0.8] |
|  |  |  |  |
| Parent (CPRS-R) Total |  |  |  |
|     1100 hrs | <0.0001 | -12.7 [-18.8 to -6.6] | -9.3 [-15.4 to -3.1] |
|     1500 hrs | <0.0001 | -12.4 [-18.6 to -6.2] | -7.0 [-13.3 to -0.7] |
| Average daily total | <0.0001 | -13.4 [-19.4 to -7.4] | -8.5 [-14.6 to -2.6] |
|  |  |  |  |
| Clinician (CGI –  1 or 2) | <0.0001 | 71.9% vs 23.5% | 66.3% vs 23.5% |
| Parent (PGA – 1 or 2) | <0.0001 | 67.8% vs 24.7% | 60.7% vs 24.7% |
| †MTS vs Placebo only |  |  |  |

## Study 302 Efficacy Summary

- MTS, worn for 9 hours, reduces symptoms of ADHD based on assessments by
- clinicians
- teachers
- parents
- Statistically significant improvement in all primary and secondary efficacy endpoints

## MTS Clinical Development Program Efficacy Conclusions

- MTS with a 9-hour target wear time demonstrated significant efficacy in laboratory classroom and outpatient settings
- Improvements in behavior are present within 2 hours of patch application and persist for 3 hours after patch removal
- Improvements ADHD symptoms and behavior reported by
- Trained observers
- Teachers
- Parents
- Clinicians

## MTS Safety Evaluations

- Raymond D. Pratt, MD
- Vice President, Clinical Development
- Shire Pharmaceuticals

## Safety Evaluations MTS Program

- Spontaneous and Elicited AEs
- No Deaths
- Clinical Laboratory Evaluations
- No Clinically Relevant Lab Abnormalities
- Physical Examinations, Vital Signs, ECGs
- No Clinically Relevant Abnormalities
- AE pattern similar in studies 201 and 302
- MPH-related
- Study 302- double-blind, placebo controlled with reference to Concerta®
- Long-term study N-021
- Growth Effects

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI
- Headache
- Tics
- Appetite AEs
- Weight and Growth
- Sleep Effects
- Dermal Evaluations

## AEs in 12-Hour MTS Studies

|  | Study 010 |  | Study 018 |  | Total 12-Hour |  |
| --- | --- | --- | --- | --- | --- | --- |
| COSTART | MTS 
N=101
(%) | PTS
N=109
(%) | MTS 
N=106
(%) | PTS
N=105
(%) | MTS N=207
(%) | PTS
N=214
(%) |
| Anorexia | 17 | 2 | 50 | 2 | 34 | 2 |
| Decreased appetite | NR | NR | NR | NR | NR | NR |
| Weight decreased | 1 | 0 | 10 | 1 | 6 | 0 |
| Insomnia | 17 | 3 | 29 | 5 | 23 | 4 |
| Nausea | 1 | 4 | 3 | 2 | 2 | 3 |
| Vomiting | 3 | 7 | 8 | 4 | 5 | 6 |
| Tic/twitching | 3 | 0 | 7 | 0 | 5 | 0 |
| Headache | 14 | 6 | 17 | 12 | 15 | 8 |

## AEs in 12-Hour MTS Studies

|  | Study 010 |  | Study 018 |  | Total 12-Hour |  |
| --- | --- | --- | --- | --- | --- | --- |
| MedDRA | MTS 
N=101
(%) | PTS
N=109
(%) | MTS 
N=106
(%) | PTS
N=105
(%) | MTS N=207
(%) | PTS
N=214
(%) |
| Anorexia | 3 | 1 | 15 | 0 | 9 | 1 |
| Decreased appetite | 14 | 1 | 36 | 2 | 25 | 2 |
| Weight decreased | 1 | 0 | 10 | 1 | 6 | 0 |
| Insomnia | 17 | 3 | 29 | 5 | 23 | 4 |
| Nausea | 1 | 4 | 3 | 2 | 2 | 3 |
| Vomiting | 3 | 7 | 8 | 4 | 5 | 6 |
| Tic | 3 | 0 | 7 | 0 | 5 | 0 |
| Headache | 14 | 6 | 17 | 12 | 15 | 8 |

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI
- Headache
- Tics
- Appetite AEs
- Weight and Growth
- Sleep Effects
- Dermal Evaluations

## Most Commonly Reported Treatment-Emergent AEs (≥5% and 2x Placebo)

| Adverse Event 
(Preferred Term)
MedDRA 7.0 | Percent of subjects reporting AEs |  |  |  |
| --- | --- | --- | --- | --- |
|  | MTS 
N=98 |  | Concerta
N=91 | Placebo
N=85 |
| % of subjects with any AE |  | 75 | 69 | 58 |
| 	Decreased appetite |  | 26 | 19 | 5 |
| 	Insomnia |  | 13 | 8 | 5 |
| 	Nausea |  | 12 | 8 | 2 |
| 	Vomiting |  | 10 | 10 | 5 |
| 	Weight decreased |  | 9 | 8 | 0 |
| 	Tic |  | 7 | 1 | 0 |
| 	Affect lability |  | 6 | 3 | 0 |
| 	Nasal congestion |  | 6 | 3 | 1 |
| 	Anorexia |  | 5 | 3 | 1 |
| 	Nasopharyngitis |  | 5 | 4 | 2 |

**Most Commonly Reported Treatment-Emergent AEs (≥5% and 2x Placebo)**

## Study 302 Discontinuations

| Reason | MTSn (%) | Concerta®n (%) | Placebon (%) |
| --- | --- | --- | --- |
| Adverse event | 	7 (7.1) | 	3 (3.2) | 	1 (1.1) |
| Protocol violation | 	1 (1.0) | 	1 (1.1) | 	3 (3.4) |
| Withdrew consent | 	3 (3.1) | 	5 (5.3) | 	6 (6.8) |
| Lost to follow-up | 	2 (2.0) | 	0 | 	2 (2.3) |
| Elected OL Study | 	12 (12.0) | 	17 (18.7)  | 	32 (37.6) |
| Other | 	3 (3.1) | 	1 (1.1) | 	11 (12.5) |
| Sponsor decision | 	2 (2.0) | 	1 (1.1) | 	2 (2.3) |

## Study 302Discontinuation AEs

| Treatment | Gender /Age/Race | Dose | Adverse Event |
| --- | --- | --- | --- |
| MTS | F/6/H | 18.75 cm2 | Viral infection |
|  | F/7/W | 12.5 cm2 | Infectious mononucleosis |
|  | M/9/W | 37.5 cm2 | Application site reaction |
|  | F/9/W | 25 cm2  | Application site erythema |
|  | M/7/W | 25 cm2 | Headaches |
|  | M/10/W | 25 cm2 | Irritability, Crying |
|  | M/6/W | 25 cm2 | Facial tics |
| Concerta® | M/11/W | 18 mg | Syncope |
|  | M/12/W | 18 mg | Abdominal pain |
|  | M/6/W | 18 mg | Aggression, Anger, Headache |
| Placebo | M/9/W | – | Worsening ADHD symptoms |

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI and Headache
- Tics
- Appetite AEs
- Weight and Growth
- Sleep Effects
- Dermal Evaluations

## Study 302 GI-Related AEs

|  |  | MTS
N=98 | Concerta®
N=91 | Placebo
N=85 |
| --- | --- | --- | --- | --- |
| Abdominal Pain | Subjects (N) | 7 | 9 | 5 |
|  | Events (N) | 10 | 11 | 8 |
|  | Ongoing (N) | 3 | 1 | 0 |
|  | Duration (days) | 54 | 47 | 34 |
| Vomiting | Subjects (N) | 10 | 9 | 4 |
|  | Events (N) | 14 | 9 | 4 |
|  | Ongoing (N) | 0 | 0 | 0 |
|  | Duration (days) | 11 | 11 | 21 |
| Nausea | Subjects (N) | 12 | 7 | 2 |
|  | Events (N) | 18 | 7 | 2 |
|  | Ongoing (N) | 1 | 0 | 0 |
|  | Duration (days) | 58 | 67 | 3 |

## Study 302 CNS-Related AEs

|  |  | MTS
N=98 | Concerta®
N=91 | Placebo
N=85 |
| --- | --- | --- | --- | --- |
| Headache | Subjects (N) | 15 | 18 | 10 |
|  | Events (N) | 24 | 26 | 14 |
|  | Ongoing (N) | 1 | 2 | 1 |
|  | Duration (days) | 36 | 34 | 48 |
| Affect Lability | Subjects (N) | 6 | 3 | 0 |
|  | Events (N) | 6 | 3 | 0 |
|  | Ongoing (N) | 2 | 2 | 0 |
|  | Duration (days) | 11±12 | 29.0 | –  |

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI and Headache
- Tics
- Appetite AEs
- Weight and Growth, short and long term
- Sleep Effects
- Dermal Evaluations

## Study 302  MedDRA Coding for Tic

| Misc. Mouth Movements |  | Onset Dose | Verbatim term | Outcome |
| --- | --- | --- | --- | --- |
| MTS | M/7/W | 25 cm2 | Repetitive tongue movements | Resolved, 9 days 
dose Reduced |
| MTS
 | M/10/W | 12.5 cm2 | Tongue rotation | Ongoing – no changes  |
| Compulsion or Stereotypy |  |  |  |  |
| MTS | M/11/W | 18.75 cm2 | Chewing | Resolved, 8 days  |
| MTS | M/9/AF | 25 cm2 | Biting Lip | Ongoing – no changes  |
| MTS | M/7/W | 12.5 cm2 | Tongue biting | Resolved, 1 day  |

## Study 302  MedDRA Coding for Tic

| Tic |  | Onset Dose | Verbatim term | Outcome |
| --- | --- | --- | --- | --- |
| MTS | M/6/W | 25 cm2 | Tic | D/C Ongoing @ 30 days |
| MTS | M/8/W | 25 cm2 | Tongue Facial Tic | Resolved, 9 day |
|  |  |  |  |  |
| Concerta® | M/12/W | 54 mg | Tongue Tic | Ongoing – no changes |

## Tic in Controlled MPH Studies

- Rate Difference

**Citation**

**Year**

**MPH**

**Placebo**

- Barkley

- 1990

- 16 / 66

- 16 / 66

- Firestone

- 1998

- 4 / 32

- 1 / 32

- Kooij

- 2004

- 3 / 45

- 1 / 45

- Law

- 1999

- 10 / 51

- 2 / 12

- MTS

- 2005

- 7 / 98

- 0 / 85

- MTS OROS

- 2005

- 1 / 91

- 0 / 85

- Palumbo

- 2004

- 9 / 224

- 8 / 219

- Palumbo OROS

- 2004

- 5 / 216

- 8 / 219

- Pelham

- 1990

- 1 / 22

- 1 / 22

- Pelham

- 1991

- 2 / 22

- 1 / 22

- Pelham

- 1999

- 1 / 25

- 1 / 25

- Pelham

- 2001

- 4 / 70

- 0 / 70

- Pelham OROS

- 2001

- 0 / 70

- 0 / 70

- Plizka

- 2000

- 0 / 20

- 1 / 18

- Stein

- 2003

- 1 / 47

- 0 / 47

**Combined (15)**

**64 / 1099**

**40 / 1037**

**-0.50**

**-0.25**

**0.00**

**0.25**

**0.50**

**Placebo**

**MPH**

## Tic in Open-Label Studies

| Study | Events
(N) | Total
(N) | Events
(%) |
| --- | --- | --- | --- |
| Concerta® PI Study 1 | 39 | 432 | 8.0 |
| Concerta® PI Study 2 | 9 | 682 | 1.3 |
| Wilens 2005: Concerta® | 40 | 408 | 9.8 |
| MTS N-021 | 2 | 191 | 1.0  |
| MTS 303 | 5 | 255 | 2.0 |

## Study 302AEs Coded as Tics

- Most MTS events were transient
- 4 of 7 resolved with continuing MTS
- Only 1 discontinuation
- Symptoms mild, do not interfere with activity
- Verbatim descriptions not all tics
- Abnormal tongue and mouth movements
- Compulsions and stereotypy are common in ADHD
- Overall frequency of tics in MTS studies consistent with published data with stimulants
- Tic not a contraindication to stimulant Rx

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI and Headache
- Tics
- Appetite AEs
- Weight and Growth, short and long term
- Sleep Effects
- Dermal Evaluations

## Study 302 Appetite-Related AEs

|  |  | MTS
N=98 | Concerta® 
N=91 | Placebo
N=85 |
| --- | --- | --- | --- | --- |
| Anorexia | Subjects (N) | 5 | 3 | 0 |
|  | Events (N) | 6 | 3 | 1 |
|  | Ongoing (N) | 2 | 2 | 0 |
|  | Duration (days) | 14±14 | 7 | 3 |
| Decreased Appetite | Subjects (N) | 25 | 17 | 4 |
|  | Events (N) | 27 | 19 | 4 |
|  | Ongoing (N) | 12 | 11 | 0 |
|  | Duration (days) | 16±11 | 20±10 | 8±5 |
| Weight Loss | Subjects (N) | 9 | 7 | 0 |
|  | Events (N) | 9 | 7 | 0 |
|  | Ongoing (N) | 5 | 4 | 0 |
|  | Duration (days) | 19±13 | 17±18 | –  |

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI and Headache
- Tics
- Appetite AEs
- Weight and Growth, short and long term
- Sleep Effects
- Dermal Evaluations

## Study 302 Weight Loss 

## Study 302 Weight Changes

## AnorexiaControlled MPH Studies

## Decreased AppetiteControlled MPH Studies

## Study 302 Appetite and Weight

- MTS: higher observed N of appetite-related AEs
- Most are transient and mild
- Number of ongoing AEs similar in both MPH groups
- Actual weight loss similar in MPH groups
- Effects are typical for oral MPH products

## Growth Effects Long-Term Evaluation

- Study N-021
- 191 patients, followed for up to 3 years
- 12-hour target wear time
- Includes 50 cm2 patch
- Important to assess effects of continuous use of MTS on growth parameters

## Long-Term Growth Effects 12-Hour Wear Time

- Subjects treated with MTS continue to grow during treatment
- Growth deficits (observed/expected) in weight and height present with MTS (~12 hour wear time)
- Deficits are small after 3 years
- Short-term, weight deficits related to dose
- Prior stimulant therapy predicts smaller deficits
- Results similar to those reported for other stimulants

## Actual Growth Indices 

**Height (cm)**

**Weight (kg)**

**Body Mass Index**

## Growth Velocity as Z-Score

## Comparison to Other StimulantsHeight

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI and Headache
- Tics
- Appetite AEs
- Weight and Growth, short and long term
- Sleep Effects
- Dermal Evaluations

## Study 302Sleep-Related AEs

|  |  | MTS
N=98 | Concerta®
N=91 | Placebo
N=85 |
| --- | --- | --- | --- | --- |
| Insomnia | Subjects (N) | 13 | 7 | 4 |
|  | Events (N) | 18 | 12 | 4 |
|  | Ongoing (N) | 5 | 6 | 1 |
|  | Duration (days) | 13±10 | 11±8 | 16±14 |

## InsomniaControlled MPH Studies

**Insomnia****Controlled MPH Studies**

**Citation**

**Year**

**MPH**

**Placebo **

- Ahmann

- 1993

- 116 / 206

- 75 / 206

- Barkley

- 1990

- 28 / 82

- 18 / 82

- Biederman

- 2003

- 2 / 65

- 0 / 71

- Connors

- 1980

- 13 / 20

- 5 / 20

- Firestone

- 1998

- 17 / 32

- 19 / 32

- Greenhill

- 2002

- 11 / 155

- 4 / 161

- Kooij

- 2004

- 15 / 45

- 10 / 45

- 302 MTS

- 2005

- 13 / 98

- 4 / 85

- 302 OROS

- 2005

- 7 / 91

- 4 / 85

- Pelham

- 1999

- 7 / 25

- 3 / 25

- Pelham

- 1991

- 4 / 22

- 1 / 22

- Pelham

- 1990

- 2 / 22

- 1 / 22

- Pelham

- 2005

- 9 / 36

- 3 / 36

- Spencer

- 2005

- 25 / 104

- 7 / 42

- Stein

- 2003

- 32 / 47

- 21 / 47

**Combined (15)**

**301 / 1050**

**175 / 981**

**-0.50**

**-0.25**

**0.00**

**0.25**

**0.50**

**Placebo**

**MPH**

**Rate Difference**

## Children’s Sleep Habits Questionnaire (CSHQ)

- CSHQ for children aged 4-12 years
- Parents assess the previous week
- Assesses quality, latency, duration, habitual efficiency, disturbances and daytime dysfunction
- 33 questions: Scored as 1 to 3
- 1 (rarely occurring; never or 1 time in the week)
- 2 (sometimes occurring; 2 to 4 times in the week)
- 3 (usually occurring; 5 or more times in the week)
- Asks if the behavior is considered a specific problem

## Study 302CSHQ Scores

**CSHQ Total Score**

## Study 302Sleep-Related Events

- Insomnia associated with MPH
- Observed incidence higher in MTS group
- Most events resolve on continuing treatment
- Transient and mild in severity
- No discontinuations or dose changes
- MTS and Concerta® have little effect on sleep habits

## MTS Safety

- Overview of AEs in 12 hour wear time studies
- Overview of AEs in 9 hour wear time study
- GI and Headache
- Tics
- Appetite AEs
- Weight and Growth, short and long term
- Sleep Effects
- Dermal Evaluations

## Dermal Evaluations

- Subjects evaluated for dermal reactions at all post-baseline visits
*Adhesion Scale*
- Adhesion performance of transdermal system
*Dermal Response Scale*
- Primary skin reactions and evidence of skin irritation
*Dermal Discomfort Scale*
- Experience of discomfort and pruritus

## Week 7 Transdermal System Adhesion

**Week 7**** Transdermal System Adhesion**

**Adhesion Scale (surface attached)**
-   0:  90%
-   1:  75% but < 90%
-   2:  50% but < 75%
-   3: <50%
-   4: MTS/PTS detached

## Week 7 Dermal Response Evaluation

**Week 7 ****Dermal Response Evaluation**

**Dermal Response Scale**
-   0: no evidence of irritation
-   1: minimal erythema
-   2: definite erythema
-   3: erythema and papules
-   4: definite edema
-   5: erythema, edema, & papules
-   6: vesicular eruption
-   7: strong reaction beyond site

## Week 7Experience of Discomfort

**Week 7****Experience of Discomfort**

**Discomfort Scale**
- 0: no discomfort
- 1: mild
- 2: moderate but tolerable
- 3: severe intolerable

## Study 302Dermal Assessment

- MTS typically associated with slight to minimal erythema
- MPH a mild irritant
- Most subjects experienced no discomfort
- Few cases of mild discomfort, typically itching
- Excellent adhesion
- Few discontinuations due to application site reactions

## MTS Safety Conclusions

- Generally well tolerated
- No related serious AEs
- Few discontinuations due to AEs
- Common AEs related to stimulant effects
- Mild, transient and resolve on continued treatment
- Persisting AE incidence similar to Concerta®
- Target wear time of 9 hours reduced the incidence of anorexia and insomnia
- Skin reactions are mild
- Short and Long-term growth effects are similar to all stimulants
- Results consistent with other approved MPH products

## MTSClinical Perspective

- Sharon B. Wigal, PhDAssociate Clinical Professor of Pediatrics
- University of California, Irvine

## MTSPatients in Clinical Trials

- “ ... an investigational medicinal patch to treat ADHD...”
- Treatment-naïve children
- Children with prior stimulant exposure

## MTS Experience inLaboratory School Setting

- Ease in administration
- Ease of removal
- Level of patient/family satisfaction

## MTSParent Comments: School

- “Teacher reports the change is like night and day”
- “His teacher noticed a big difference ... like a different kid”
- “ ... much more focused and accomplishes work”

## MTSParent Comments: Home

- “Everybody comments on her improvement”
- “...my child listens, follows through on directions”
- “I can tell when the meds wear off because [child] pesters her brother”

## MTSParents Comments: Long-term Use

- “The three side effects that I have noted (loss of appetite, sleeplessness and skin irritation) have all been acceptable trade offs...  After several weeks, his appetite returned in the evening either by acclimation or by modifying our removal time to 3:30 PM... the earlier removal time also assisted in eradicating sleeplessness at bedtime.  Lastly, I have noticed far less reddening of skin (barely any) as time has passed and have not had any complaints of skin irritation for some time.”

## MTSClinical Utility Conclusions

- MTS was a viable treatment option for children with ADHD
- Ease of use
- Compliance to treatment
- Positive parent perception
- Flexibility of treatment period
- Manageable side effects

## Benefit / Risk Summary

- Raymond D. Pratt, MD

## Benefits of MTS

- Once-daily application
- Behavioral response within 2 hours
- Clinical benefits persist for at least 3 hours after patch removal
- Transdermal
- No oral dosing
- Excellent adhesion; minimal irritation
- 9-hour MPH exposure similar to oral MPH products
- Exposure controlled by patch size and wear time
- Drug delivery stops on patch removal
- Decreased risk of accidental ingestion or overdose

## Risks of MTS

- Adverse events with MTS are same as oral MPH
- MTS wear times > 9-hours might lead to a higher incidence of anorexia and insomnia
- Longer-term effects with MTS on growth parameters are similar to other psychostimulants
- Potential for sensitization and irritation with MTS
- CII substance: potential for abuse and/or diversion

## Conclusions

- MTS is a new effective delivery system for once-daily treatment of ADHD with MPH
- Onset of effect within 2 hours of application
- Duration of effect covers the school day
- Potential for customized treatment
- Positive benefit-risk balance
- Incidence of AEs similar to other MPH products

## Summary of Psychiatric AEs By Treatment: All Studies

| Study | Treatment | N | Psychosis/mania events (n) | Suicidal events (n) | Aggression events (n) |
| --- | --- | --- | --- | --- | --- |
| 021 | MTS | 191 | 3 | 1 | 3 |
| 102 | Crossover RxMTS | 34 | 0 | 0 | 0 |
| 102 | Crossover Rx Concerta® | 33 | 1 | 0 | 0 |
| 201 | Titration & Crossover Rx MTS | 93 | 0 | 0 | 3 |
| 201 | Crossover Rx Placebo | 79 | 0 | 0 | 0 |
| 302 | MTS | 98 | 0 | 0 | 3 |
| 302 | Concerta® | 91 | 1 | 0 | 1 |

## 302: Summary of Patch Wear Time by Visit – Safety Population

## Structures of Methylphenidate and Its threo-Isomers

**Structures of Methylphenidate and Its *****threo-*****Isomers**

- The 2 asymmetric carbon atoms are denoted with asterisks.

**d-*****threo***
**(2R:2**** ́****R)**

**l-*****threo***
**(2S:2**** ́****S)**

- Methylphenidate

## Differences in the Exposure to l-threo-Methylphenidate after Oral or Transdermal Administration of Parent Racemate

***dl*****-*****threo*****-methylphenidate**
**(*****dl*****-*****threo*****-MPH)**

**             ****Oral route**
**Plasma C max **
**[*****d*****-*****threo*****-MPH****]:[*****l*****-*****threo*****-MPH****]**
**Ritalin IR****®**** ****	****5.0**** ****: ****1.0****a**
**Ritalin SR****®**** ****	****10.0**** ****: ****1.0****b**
**Concerta****®****	****40.0**** ****: ****1.0****c**

**MTS transdermal patch**
**(12.5 – 37.5 cm patch/9hr)**
**[*****d*****-*****threo*****-MPH****]:[*****l*****-*****threo*****-MPH****]**
**SPD485-102****	****1.6**** ****: ****1.0****d**
**SPD485-201****	****1.6**** ****: ****1.0****d**
**SPD485-302 ****	****1.9**** ****: ****1.0****d**

- aSrinivas *et al* (1997); bHubbard *et al* (1989); cModi *et al* (2000); dSponsor’s data obtained in paediatric patients

## Catecholamine Mechanisms Efficacy vs Side-Effects

**Catecholamine Mechanisms ****Efficacy vs Side-Effects**

**Efficacy in ADHD**
- Cognitive function 	
- Attentiveness 	
- Distractibility 	
- Hyperactivity	
- Behavioural 	
- disruption

**Side-effects**
- Insomnia 	
- BP/HR 	
- Abdominal cramps 	
- Tics	
- Appetite	
- Body weight	
- Growth rate	

**Atomoxetine**

**Norepinephrine**

**Methylphenidate**
**and its isomers**

**Mixed profile**

**Bupropion**

**Dopamine**

## Monoamine Reuptake Inhibition Profiles of the Enantiomers of threo-Methylphenidate

- Data for inhibition of tritiated uptake into rat synaptosomes taken from; aRichelson & Pfenning (1984); bAndersen (1989); cDeutsch et al (1996)/Schweri et al (2002); dFerris et al (1972); ePatrick et al (1987)

## Intracerebral Microdialysis Experiments in Freely-Moving Rats Confirms the Reuptake Inhibition Profiles of Methylphenidate’s Enantiomers

**Norepinephrine, Frontal cortex**

**Dopamine, striatum**

## The Behavioural Effects of the Isomers of Methylphenidate Mirror Their Neurochemical Profiles

- Saline (ip)

- d-Methylphenidate (1 mg/kg ip)

- d-Methylphenidate (10 mg/kg ip)

- l-Methylphenidate (10 mg/kg ip)

## Clinical Studies

- Srinivas *et al* (1992): placebo-controlled, cross-over study in children with ADHD.
*d*-MPH (5 mg) as efficacious as *dl*-MPH (10 mg)
*l*-MPH (5 mg) was inactive
- Wigal *et al* (2004): placebo-controlled, dose-titration trial in children with ADHD.
*d*-MPH delivered efficacy and side-effects equivalent to *dl*-MPH at approximately half the dose (18.2 versus 32.1 mg/day)

## Summary and Conclusions

*d-Threo-*methylphenidate (*d*-MPH) ≥10x potent than the *l-*isomer (*l*-MPH)
*d*-MPH is the predominant driver of efficacy and side-effects
- The lower potency and plasma concentrations of *l*-MPH dictate that it contributes at most 5-10% of the efficacy and side-effects of *dl*-MPH in the MTS patch
- Clinical data support the hypothesis that whilst *l-*MPH delivers no discernable clinical benefit, its presence in racemic MPH preparations does not adversely impact on the side-effect liability of such products

## Dosing Diary

## Mean Plasma d-MPH Concentration vs Time Plots for Caucasians

**MTS06 25cm****2**

**MTS08 25cm****2**

**MTS10 25cm****2**

**Concerta****® ****36 mg**

**0**

**0**

**5**

**10**

**15**

**20**

**25**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**Time after dosing (hours)**

***d*****-MPH (ng/mL)**

- Study 101: n=9 MTS; n = 10 Concerta®

**Mean Plasma *****d-*****MPH Concentration vs Time Plots for Caucasians**

**JMV:**
**Colors need to be changed**

## Irritation Analysis (Study N17-020)

| Parameter | Irritation Analysis |  | Irritation Analysis |  |
| --- | --- | --- | --- | --- |
|  | MTS | Placebo PTS | MTS | Negative Control-Saline |
| Mean | 2.06 | 1.62 | 2.06 | 0.78 |
| Std Dev | 0.56 | 0.65 | 0.56 | 0.57 |
| N | 145 | 145 | 145 | 145 |
| Adjusted Difference | 0.03 |  | 1.08 |  |
| 95% Upper Confidence* | 0.1536† |  | 1.2047† |  |
| * MTS is equivalent to the comparator (placebo or control) if 95% upper confidence bound is less than or equal to zero.
† MTS is more irritating than the placebo and the control. |  |  |  |  |

## Number of Subjects Who Underwent Challenge and Rechallenge Reactions (Study N17-020)

| Category | N |
| --- | --- |
| Participating in Challenge Period | 133* |
| Participating in Rechallenge Period | 36 |
| With Irritation at Rechallenge Period | 16 |
| With Sensitization based on Challenge and Rechallenge Periods | 17 |
| With Sensitization based on Challenge Alone | 1 |
| With Potential Sensitization to MTS, but Rechallenge Needed | 8 |
| With Sensitization based on Incomplete Challenge Period | 1 |
| *One subject (No. 331) only had a 48-hour evaluation |  |

## Treatment-Emergent Adverse Events in 5% of All Subjects Long-Term Pediatric Population by Time

**Treatment-Emergent Adverse Events in ********5% of All Subjects Long-Term Pediatric Population by Time**

| Body System
COSTART Term* | Time of Event Onset in Days |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | 1-29 (n=322) | 30-59 (n=286) | 60-89 (n=255) | 90-119 (n=171) | 120-149 (n=143) | 150-179 (n=128) | 180-209 (n=117) |
| Any Adverse Event | 288 (89) | 209 (73) | 194 (76) | 127 (74) | 82 (57) | 50 (39) | 36 (31) |
| Headache | 35 (11) | 13 (5) | 9 (4) | 10 (6) | 8 (6) | 5 (4) | 3 (3) |
| Abdominal Pain | 26 (8) | 9 (3) | 4 (2) | 5 (3) | 0 | 2 (2) | 2 (2) |
| Anorexia | 66 (20) | 13 (5) | 12 (5) | 5 (3) | 3 (2) | 2 (2) | 1 (1) |
| Vomiting | 16 (5) | 4 (1) | 6 (2) | 3 (2) | 1 (1) | 2 (2) | 0 |
| Weight Loss | 25 (8) | 4 (1) | 2 (1) | 3 (2) | 0 | 0 | 0 |
| Insomnia | 54 (17) | 10 (3) | 5 (2) | 0 | 1 (1) | 0 | 1 (1) |
| Nervousness | 19 (6) | 5 (2) | 2 (1) | 2 (1) | 0 | 2 (2) | 0 |
| Application Site Reaction | 255 (79) | 174 (61) | 165 (65) | 109 (64) | 66 (46) | 32 (25) | 18 (15) |

## Slide 117