Safety, Pharmacokinetics (PK), and Efficacy of Buprenorphine Transdermal System (BTDS) in Children

• Sponsor: Purdue Pharma LP (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01324570
• Collaborator: (none)
• Enrollment: 41
• Locations: 22
• Arm: 1
• Duration (Months): 58
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize the safety, PK, and efficacy of BTDS in patients of ages 7 to 16 years.

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: Buprenorphine transdermal system	Phase 3

Detailed Description

A study of safety, PK, and efficacy of BTDS in patients of ages 7 to 16 years, inclusive, who require continuous opioid analgesia for moderate to severe pain.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter Study of the Safety, Pharmacokinetics, and Efficacy of Buprenorphine Transdermal System (BTDS) in Children From 7 to 16 Years of Age, Inclusive, Who Require Continuous Opioid Analgesia for Moderate to Severe Pain
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Overall BTDS Buprenorphine transdermal system	Drug: Buprenorphine transdermal system; Buprenorphine transdermal system 2.5 mcg/h, 5 mcg/h, 10 mcg/h or 20 mcg/h applied transdermally for 7-day wear.; Other Names: Butrans

Outcome Measures

Primary Outcome Measures

1. The Number of Participants With Adverse Events as a Measure of Safety [Up to 28 weeks]

   Safety assessments consisted of reports of AEs, vital signs (blood pressure, pulse rate, respiratory rate, and temperature), weight, hemoglobin-oxygen saturation measured by pulse oximetry (SpO2), clinical laboratory tests, somnolence (assessed by the University of Michigan Sedation Scale [UMSS]), conventional 12-lead electrocardiograms (ECGs), and 24-hour digital 12-lead ECGs (Holter monitor). Safety variables were summarized descriptively within age group for the safety population.

2. Pharmacokinetics (PK) of Buprenorphine Following Transdermal Administration: Apparent Clearance (CL/F) [Day 1, end of week 1, days 9/10, end of week 2, and end of week 4 or at discontinuation prior to end of study visit]

   The population PK (PopPK) of BTDS buprenorphine in pediatric patients ages 7 to 16 years was described by a 2-compartment model with sequential zero- and first-order absorption from the patch. A fixed allometric relationship was used to describe the effects of changes in ideal body weight (IBW) across pediatric patients on all clearance and volume parameters. Given the sparse sample collections, small sample size, and complexity of the absorption process with the patch formulation, this PopPK model was fit to the pediatric data using nonlinear mixed effects modeling (NONMEM) Bayes method with selective use of priors from previous adult PopPK results. Estimates of fixed effects from the final model were used to calculate the CL/F after patch dosing given the covariate distribution in the PopPK dataset and the typical weights from children in the National Health and Nutrition Examination Survey (NHANES) dataset.

3. Pharmacokinetics (PK) of Buprenorphine Following Transdermal Administration: Apparent Volume of Distribution (Vc/F) [Day 1, end of week 1, days 9/10, end of week 2, and end of week 4 or at discontinuation prior to end of study visit]

   The population PK (PopPK) of BTDS buprenorphine in pediatric patients ages 7 to 16 years was described by a 2-compartment model with sequential zero- and first-order absorption from the patch. A fixed allometric relationship was used to describe the effects of changes in ideal body weight (IBW) across pediatric patients on all clearance and volume parameters. Given the sparse sample collections, small sample size, and complexity of the absorption process with the patch formulation, this PopPK model was fit to the pediatric data using nonlinear mixed effects modeling (NONMEM) Bayes method with selective use of priors from previous adult PopPK results. Estimates of fixed effects from the final model were used to calculate the Vc/F after patch dosing given the covariate distribution in the PopPK dataset and the typical weights from children in the National Health and Nutrition Examination Survey (NHANES) dataset.

Secondary Outcome Measures

1. Pain Right Now Assessment by Patients Aged 7 to 11 Years, Inclusive [Up to 24 weeks]

   Pain right now was assessed using the Faces of Pain Scale-Revised (FPS-R). The FPS-R is a horizontal row of 6 faces representing pain intensity, with "no hurt" at the far left and "hurts worst" at the far right; the intensities are scored as 0, 2, 4, 6, 8, or 10. A score of 0=no pain, and 10=very much pain. For screening to week 4, pain right now was assessed at 30 minutes before initial BTDS application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline score was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. The study measured pain right now for weeks 6-24 once a week at approximately 8 PM while on treatment; however, no patients in this age group were treated beyond week 12.

2. Pain Right Now Assessment by Patients Aged 12 to 16 Years, Inclusive [Up to 24 weeks]

   Pain right now was assessed using a 100-mm visual analogue scale (VAS). The 100-mm VAS is a 100-mm line with 1 end marked as "no pain" and the other marked as "pain as bad as it could be." The patient was asked to make a mark on that line indicating his or her level of pain. Pain right now score was defined as the distance (in mm) from the "no pain" end to the patient's mark; 0=no pain and bigger numbers indicate more pain. For screening to week 4, pain right now was assessed 30 minutes before initial BTDS application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. For weeks 6-24, pain right now was measured once a week at approximately 8 PM.

3. Parent/Caregiver-assessed Global Impression of Change (PGIC) [End of treatment (week 24) or early discontinuation visit]

   The PGIC rating score variable was collected on a 7-point scale ranging from 1 to 7 (where 1 = very much improved; and 7 = very much worse). The PGIC is designed to assess overall satisfaction with the treatment. The PGIC score was summarized using the number and percent of patients in each of the 7 possible response categories overall and by age group. PGIC was assessed by the parent/caregiver at the end of treatment visit or early discontinuation visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 16 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria include:

• Male and female patients, 7 to 16 years of age, inclusive, with malignant and/or nonmalignant moderate to severe pain requiring or anticipated to require continuous, around-the-clock, opioid treatment for at least 2 weeks (based on the investigator's judgment);

• Patients must have written informed consent provided by the parent or legal guardian and assent provided by the patient, when appropriate;

• Patients on incoming opioids must be taking ≤ 80 mg/day morphine or equivalent if aged 12 to 16 years or ≤ 40 mg/day morphine or equivalent if aged 7 to 11 years prior to the screening visit;

• Patients and patient's parent/caregiver must be compliant with the protocol, ie, must be able to perform study assessments and understand and complete the age-appropriate scale to rate pain intensity. Patients must not have a cognitive developmental delay or any other condition that would preclude them from completing the age-appropriate pain scale.

Exclusion Criteria include:

• Patients who are allergic to buprenorphine or have a history of allergies to other opioids (this criterion does not include patients who have experienced common opioid side effects [eg, nausea, constipation]) or who have allergies or other contraindications to transdermal delivery systems or patch adhesives;

• Patients with a dermatological disorder, including burn and skin graft sites, at any relevant patch application site that would preclude proper placement and/or rotation of BTDS patches;

• Patients with evidence of impaired renal function;

• Patients with hepatic impairment;

• Patients with history of seizures;

• Patients with intracranial pressure;

• Patients who have a history of sleep apnea within the past year;

• Patients who require mechanical ventilation during study treatment period, are cyanotic, or who have unstable respiratory disease;

• Patients with clinically significant structural heart disease or a pacemaker;

• Patients with clinically unstable cardiac disease;

• Patients who receive or anticipate to receive investigational medication/therapy during study drug treatment period.

Other protocol-specific inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Long Beach Memorial Medical Center	Long Beach	California	United States	90806
2	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
3	Children's Health Center	Los Angeles	California	United States	90095-1752
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
6	Howard University Hospital	Washington, D.C.	District of Columbia	United States	20060
7	Jackson Memorial Hospital / University of Miami	Miami	Florida	United States	33136
8	Children's Healthcare of Atlanta at Egleston	Atlanta	Georgia	United States	30322
9	University of Illinois Hospital and Health Sciences System	Chicago	Illinois	United States	60612
10	Kosair Charities Pediatric Clinical Research Unit - University of Louisville	Louisville	Kentucky	United States	40202
11	Willis-Knighton Physician Network	Shreveport	Louisiana	United States	71118
12	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
13	WCMC, Department of Pediatrics - Hematology/Oncology	New York	New York	United States	10065
14	Stony Brook University Hospital	Stony Brook	New York	United States	11794
15	Children's Hospital at Montefiore	The Bronx	New York	United States	10467
16	Vidant Medical Center	Greenville	North Carolina	United States	27834
17	The Center for Clinical Research - Carolina Pain Institute	Winston-Salem	North Carolina	United States	27103
18	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
19	Rhode Island Hospital, Department of Pediatrics	Providence	Rhode Island	United States	02903
20	Medical University of South Carolina	Charleston	South Carolina	United States	29425
21	Children's Blood and Cancer Center	Austin	Texas	United States	78723
22	Road Runner Research, Ltd.	San Antonio	Texas	United States	78258

Sponsors and Collaborators

• Purdue Pharma LP

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Product Information

Publications

None provided.

• Responsible Party: Purdue Pharma LP
• ClinicalTrials.gov Identifier: NCT01324570
• Other Study ID Numbers: BUP3031; 2010-021954-21
• First Posted: Mar 29, 2011
• Last Update Posted: Jul 6, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Purdue Pharma LP: Pain; Opioid; Analgesia; Moderate to severe pain
• Additional relevant MeSH terms: Buprenorphine

Study Results

Participant Flow

Recruitment Details	First Patient First Visit: 23-July-2012; Last Patient Last Visit: 23-May-2016. The study was conducted at 33 study centers in the United States

Arm/Group Title	7 to 11 Years	12 to 16 Years
Arm/Group Description	Children 7 to 11 years of age	Children 12 to 16 years of age
Period Title: Overall Study
STARTED	6	35
COMPLETED	2	21
NOT COMPLETED	4	14

Baseline Characteristics

Arm/Group Title	7 to 11 Years	12 to 16 Years	Total
Arm/Group Description	Children 7 to 11 years of age	Children 12 to 16 years of age	Total of all reporting groups
Overall Participants	6	35	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.3 (1.21)	14.6 (1.31)	14.0 (1.99)
Sex: Female, Male (Count of Participants)
Female	3 50%	23 65.7%	26 63.4%
Male	3 50%	12 34.3%	15 36.6%
Race/Ethnicity, Customized (Count of Participants)
White	3 50%	18 51.4%	21 51.2%
Black or African American	2 33.3%	15 42.9%	17 41.5%
Other	1 16.7%	2 5.7%	3 7.3%

Outcome Measures

1. Primary Outcome

Title	The Number of Participants With Adverse Events as a Measure of Safety
Description	Safety assessments consisted of reports of AEs, vital signs (blood pressure, pulse rate, respiratory rate, and temperature), weight, hemoglobin-oxygen saturation measured by pulse oximetry (SpO2), clinical laboratory tests, somnolence (assessed by the University of Michigan Sedation Scale [UMSS]), conventional 12-lead electrocardiograms (ECGs), and 24-hour digital 12-lead ECGs (Holter monitor). Safety variables were summarized descriptively within age group for the safety population.
Time Frame	Up to 28 weeks

Outcome Measure Data

Analysis Population Description

The safety population (N=41) was the group of patients who received at least 1 dose of study drug during the study.

Arm/Group Title	7 to 11 Years	12 to 16 Years
Arm/Group Description	Children 7 to 11 years of age	Children 12 to 16 years of age
Measure Participants	6	35
Serious adverse events	5 83.3%	5 14.3%
All other adverse events in ≥ 5% of patients	6 100%	20 57.1%

2. Primary Outcome

Title	Pharmacokinetics (PK) of Buprenorphine Following Transdermal Administration: Apparent Clearance (CL/F)
Description	The population PK (PopPK) of BTDS buprenorphine in pediatric patients ages 7 to 16 years was described by a 2-compartment model with sequential zero- and first-order absorption from the patch. A fixed allometric relationship was used to describe the effects of changes in ideal body weight (IBW) across pediatric patients on all clearance and volume parameters. Given the sparse sample collections, small sample size, and complexity of the absorption process with the patch formulation, this PopPK model was fit to the pediatric data using nonlinear mixed effects modeling (NONMEM) Bayes method with selective use of priors from previous adult PopPK results. Estimates of fixed effects from the final model were used to calculate the CL/F after patch dosing given the covariate distribution in the PopPK dataset and the typical weights from children in the National Health and Nutrition Examination Survey (NHANES) dataset.
Time Frame	Day 1, end of week 1, days 9/10, end of week 2, and end of week 4 or at discontinuation prior to end of study visit

Outcome Measure Data

Analysis Population Description

The full analysis population (FAP) for PK consisted of patients who received study drug and had at least 1 valid quantifiable PK blood sample (N=41).Three patients had no quantifiable plasma buprenorphine concentration measurements and were not included in the PK analysis.The final buprenorphine pediatric PK analysis dataset comprised 38 patients.

Arm/Group Title	Population PK Analysis Set
Arm/Group Description	Children 7 to 16 years of age (reference patient with IBW of 70 kg)
Measure Participants	38
Mean (95% Confidence Interval) [Liters/hour]	293

3. Secondary Outcome

Title	Pain Right Now Assessment by Patients Aged 7 to 11 Years, Inclusive
Description	Pain right now was assessed using the Faces of Pain Scale-Revised (FPS-R). The FPS-R is a horizontal row of 6 faces representing pain intensity, with "no hurt" at the far left and "hurts worst" at the far right; the intensities are scored as 0, 2, 4, 6, 8, or 10. A score of 0=no pain, and 10=very much pain. For screening to week 4, pain right now was assessed at 30 minutes before initial BTDS application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline score was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. The study measured pain right now for weeks 6-24 once a week at approximately 8 PM while on treatment; however, no patients in this age group were treated beyond week 12.
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

The full analysis population (FAP) was the group of patients who received at least 1 dose of the study drug during the study.

Arm/Group Title	7 to 11 Years
Arm/Group Description	Children 7 to 11 years of age
Measure Participants	5
Baseline	2.80 (1.497)
Week 1	3.49 (1.768)
Week 2	2.98 (1.871)
Week 3	0.29 (0.000)
Week 4	0.00 (0.000)
Week 5	0.00 (NA)
Week 6	0.00 (NA)
Week 7	0.00 (NA)
Week 8	0.00 (NA)
Week 9	0.00 (NA)
Week 10	0.00 (NA)
Week 11	0.00 (NA)
Week 12	0.00 (NA)

4. Secondary Outcome

Title	Pain Right Now Assessment by Patients Aged 12 to 16 Years, Inclusive
Description	Pain right now was assessed using a 100-mm visual analogue scale (VAS). The 100-mm VAS is a 100-mm line with 1 end marked as "no pain" and the other marked as "pain as bad as it could be." The patient was asked to make a mark on that line indicating his or her level of pain. Pain right now score was defined as the distance (in mm) from the "no pain" end to the patient's mark; 0=no pain and bigger numbers indicate more pain. For screening to week 4, pain right now was assessed 30 minutes before initial BTDS application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. For weeks 6-24, pain right now was measured once a week at approximately 8 PM.
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

The FAP was the group of patients who received at least 1 dose of the study drug during the study.

Arm/Group Title	12 to 16 Years
Arm/Group Description	Children 12 to 16 years of age
Measure Participants	35
Baseline	46.6 (4.55)
Week 1	43.1 (4.03)
Week 2	41.6 (4.67)
Week 3	36.0 (4.82)
Week 4	34.7 (5.09)
Week 5	30.3 (5.90)
Week 6	28.0 (6.56)
Week 7	29.1 (5.56)
Week 8	34.3 (7.17)
Week 9	27.3 (5.83)
Week 10	36.7 (5.83)
Week 11	35.7 (8.15)
Week 12	42.5 (8.31)
Week 13	36.0 (7.99)
Week 14	38.2 (8.67)
Week 15	30.5 (6.52)
Week 16	38.7 (6.94)
Week 17	30.9 (5.74)
Week 18	37.7 (6.88)
Week 19	37.4 (5.50)
Week 20	35.6 (7.48)
Week 21	32.4 (5.97)
Week 22	38.1 (5.84)
Week 23	38.7 (6.42)
Week 24	36.5 (5.35)

5. Secondary Outcome

Title	Parent/Caregiver-assessed Global Impression of Change (PGIC)
Description	The PGIC rating score variable was collected on a 7-point scale ranging from 1 to 7 (where 1 = very much improved; and 7 = very much worse). The PGIC is designed to assess overall satisfaction with the treatment. The PGIC score was summarized using the number and percent of patients in each of the 7 possible response categories overall and by age group. PGIC was assessed by the parent/caregiver at the end of treatment visit or early discontinuation visit.
Time Frame	End of treatment (week 24) or early discontinuation visit

Outcome Measure Data

Analysis Population Description

The full analysis population (FAP) (N=40) was the group of patients who received at least 1 dose of the study drug during the study; however data was provided for only 38 patients for this outcome measure.

Arm/Group Title	7 to 11 Years	12 to 16 Years
Arm/Group Description	Children 7 to 11 years of age	Children 12 to 16 years of age
Measure Participants	4	34
Participants Represented	4 66.7%	34 97.1%
1 = Very much improved	1 16.7%	6 17.1%
2 = Much improved	0 0%	12 34.3%
3 = Minimally improved	0 0%	8 22.9%
4 = No change	2 33.3%	5 14.3%
5 = Minimally worse	1 16.7%	2 5.7%
6 = Much worse	0 0%	1 2.9%
7 = Very much worse	0 0%	0 0%

6. Primary Outcome

Title	Pharmacokinetics (PK) of Buprenorphine Following Transdermal Administration: Apparent Volume of Distribution (Vc/F)
Description	The population PK (PopPK) of BTDS buprenorphine in pediatric patients ages 7 to 16 years was described by a 2-compartment model with sequential zero- and first-order absorption from the patch. A fixed allometric relationship was used to describe the effects of changes in ideal body weight (IBW) across pediatric patients on all clearance and volume parameters. Given the sparse sample collections, small sample size, and complexity of the absorption process with the patch formulation, this PopPK model was fit to the pediatric data using nonlinear mixed effects modeling (NONMEM) Bayes method with selective use of priors from previous adult PopPK results. Estimates of fixed effects from the final model were used to calculate the Vc/F after patch dosing given the covariate distribution in the PopPK dataset and the typical weights from children in the National Health and Nutrition Examination Survey (NHANES) dataset.
Time Frame	Day 1, end of week 1, days 9/10, end of week 2, and end of week 4 or at discontinuation prior to end of study visit

Outcome Measure Data

Analysis Population Description

The full analysis population (FAP) for PK consisted of patients who received study drug and had at least 1 valid quantifiable PK blood sample (N=41).Three patients had no quantifiable plasma buprenorphine concentration measurements and were not included in the PK analysis.The final buprenorphine pediatric PK analysis dataset comprised 38 patients.

Arm/Group Title	Population PK Analysis Set
Arm/Group Description	Children 7 to 16 years of age (reference patient with IBW of 70 kg)
Measure Participants	38
Mean (95% Confidence Interval) [Liters]	2350

Adverse Events

Time Frame	Non-serious treatment-emergent adverse events (TEAEs) were collected from the initiation of treatment with study drug up to 7 days after the last dose of study drug. Serious adverse events (SAEs) were collected from the signing of the informed consent form through 30 days of the last dose of study drug.
Adverse Event Reporting Description	For the assessment of SAEs and TEAEs, the analysis population included all patients exposed to at least 1 dose of study drug (ie, safety population). An SAE of pneumohemothorax occurred in 1 patient during screening and an SAE of sickle cell pain crisis occurred in 1 patient during screening. Both patients were considered screen failures, were not treated with study drug, and were not included in the safety population.
Arm/Group Title	7 to 11 Years		12 to 16 Years
Arm/Group Description	Children 7 to 11 years of age		Children 12 to 16 years of age
All Cause Mortality
	7 to 11 Years		12 to 16 Years
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/35 (0%)
Serious Adverse Events
	7 to 11 Years		12 to 16 Years
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		5/35 (14.3%)
Blood and lymphatic system disorders
Anaemia	1/6 (16.7%)		0/35 (0%)
Cardiac disorders
Atrioventricular Block First Degree	1/6 (16.7%)		0/35 (0%)
Congenital, familial and genetic disorders
Hereditary Angioedema	0/6 (0%)		1/35 (2.9%)
Sickle Cell Anaemia With Crisis	0/6 (0%)		2/35 (5.7%)
Gastrointestinal disorders
Crohn's Disease	1/6 (16.7%)		0/35 (0%)
General disorders
Fatigue	1/6 (16.7%)		0/35 (0%)
Infections and infestations
Appendicitis	1/6 (16.7%)		0/35 (0%)
Osteomyelitis Chronic	0/6 (0%)		1/35 (2.9%)
Metabolism and nutrition disorders
Malnutrition	1/6 (16.7%)		0/35 (0%)
Musculoskeletal and connective tissue disorders
Osteonecrosis	1/6 (16.7%)		0/35 (0%)
Nervous system disorders
Hypersomnia	1/6 (16.7%)		0/35 (0%)
Migraine	0/6 (0%)		1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	7 to 11 Years		12 to 16 Years
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		20/35 (57.1%)
Blood and lymphatic system disorders
Leukocytosis	1/6 (16.7%)		0/35 (0%)
Neutropenia	1/6 (16.7%)		0/35 (0%)
Cardiac disorders
Sinus Tachycardia	1/6 (16.7%)		0/35 (0%)
Congenital, familial and genetic disorders
Sickle Cell Anaemia With Crisis	0/6 (0%)		2/35 (5.7%)
Gastrointestinal disorders
Constipation	1/6 (16.7%)		1/35 (2.9%)
Nausea	1/6 (16.7%)		7/35 (20%)
Vomiting	1/6 (16.7%)		3/35 (8.6%)
Diarrhoea	0/6 (0%)		2/35 (5.7%)
General disorders
Application Site Pruritus	0/6 (0%)		7/35 (20%)
Application Site Irritation	1/6 (16.7%)		4/35 (11.4%)
Fatigue	1/6 (16.7%)		1/35 (2.9%)
Infections and infestations
Clostridium Difficile Colitis	1/6 (16.7%)		0/35 (0%)
Investigations
Electrocardiogram QT Prolonged	0/6 (0%)		2/35 (5.7%)
Musculoskeletal and connective tissue disorders
Back Pain	0/6 (0%)		3/35 (8.6%)
Arthralgia	1/6 (16.7%)		2/35 (5.7%)
Pain in Extremity	0/6 (0%)		2/35 (5.7%)
Juvenile Arthritis	1/6 (16.7%)		0/35 (0%)
Nervous system disorders
Migraine	0/6 (0%)		2/35 (5.7%)
Headache	1/6 (16.7%)		5/35 (14.3%)
Somnolence	1/6 (16.7%)		5/35 (14.3%)
Dizziness	1/6 (16.7%)		2/35 (5.7%)
Paresthesia	0/6 (0%)		2/35 (5.7%)
Sedation	1/6 (16.7%)		0/35 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/6 (16.7%)		0/35 (0%)

Limitations/Caveats

Patient recruitment in the younger age group was difficult and the sample size is smaller than the older age group. This limitation should be a consideration when interpreting the data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.