Conditions: Chronic Pain
Keywords: Pediatric
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
This pediatric study is designed to provide safety information, dosing guidelines, and a pharmacokinetic (PK) evaluation of once-daily hydromorphone hydrochloride (HCl) extended-release (ER) tablets in children with chronic painful conditions who are "opioid-tolerant" prior to enrollment under the Pediatric Research Equity Act (PREA) of 2003.

Detailed description:

Arms:
arm 1: Participants receive Hydromorphone HCl ER Tablets (4-16 mg, based on standard conversion ratios for common opioids)

Interventions: intervention 1: Hydromorphone HCl ER Tablets
Intervention descriptions: intervention 1: Hydromorphone hydrochloride (HCl) extended release tablet

Protocol document:
Prot_SAP_000.pdf: 
Mallinckrodt 
Pharmaceuti
ca Is 
(hydromorphOne HCI) G: 
-   ·-
-
0110101lty 
CLINICAL STUDY PROTOCOL 
An Open-Label, Safety and Pharmacokinetic Study of 
Hydromorphone Hydrochloride Extended-Release Tablets 
(Once-Daily Hydromorphone) in Opioid-Tolerant 
Pediatric Subjects with Chronic Pain 
IND No
:
-
Protocol Number: COV02520124 
Phase: 3b 
Date of Original Protocol: 14 October 2010 
Date of Second Version: 31October2011 
Date of Amendment 1: 
Date of Amendment 2: 
Date of Amendment 3: 
Date of Amendment 4: 
17 May 2012 
09 December 2013 
17 March 2014 
17 November 2017 
Sponsor: 
Mallinckrodt Pharmaceuticals 
1425 Route 206 
Bedminster, NJ 07921 
NCT02321319
NCT02321319
NCT02321319
NCT02321319


Hydromorphone HCl Extended-Release Tablets (Once Daily Hydromorphone) 
Protocol COV02520124 ancorporating Amendments 1, 2, 3, and 4) 
7 SYNOPSIS 
Page 27 of78 
Tllis is a synopsis
. Tile body of 
t/1e protocol must be referenced f or tile complete study information. 
Study Title: An Open-Label. Safety and Phannacokinetic Study ofHydromorphone Hydrochloride 
Extended-Release Tablets (Once-Daily Hydromorphone) in Opioid-Tolerant Pediatric Subjects with 
Chronic Pain 
Protocol 
I 
COV02520124 
Phase I 
3b 
I 
Type I 
Inte1ventional 
Number 
Condition/Disease: Subjects 7 to 17 years old with chronic pain secondaly to cancer and/or noncancer 
origins. 
Approximate 
Number of Subjects 
100 
Duration of Subject 
Approximately 28 days including an 
Participation 
optional safety obse1vation 
extension of up to 3 weeks. 
Number of Study 
Up to 10 
Duration of Study 
Five years. 
Centers 
Rationale: This pediatric study is designed to provide safety infonnation, 
dosing guidelines, and a 
phannacokinetic (PK) evaluation of once-daily hydromorphone hydrochloride (HCl) extended-release 
(ER) tablets in children with chronic painful conditions who are "opioid-tolerant" p1ior to emollment 
under the Pediatric Research Equity Act of 2003. 
Population PK techniques will be utilized in order to 
better m1derstand the PK profile of once-daily hydromorphone HCl ER tablets in pediatric subjects while 
linliting the number and timing of sample collections. 
Objectives: 
Prim!![Y 
The primaiy objective of this study is to evaluate the safety (based on vital signs, 
pulse oximetiy, clinical 
laborat
o1y  assessments, and adverse events [AEs]) of once-daily dosing ofhydromorphone HCl ER 
tablets in pediatiic subjects between 7 and 17 years old with pain seconda1y to cancer and/or noncancer 
origins. 
Secondm 
The secondary objectives of this study ai·e to evaluate the following parameters: 
• PK data following initial and steady-state dosing in subjects between 7 and 17 years old (in even 
distribution of age strata, 
for example, 
age 7 to less than 12 years ai1d age 12 to 17 years). 
• Effectiveness (based on pain intensity scores) in controlling pain 
• Quality of life utilizing a validated pediatric testing insti111llent (Pediatiic Quality of Life 
[PedsQL]). 
Design: This is ai1 open-label, multidose. 
multicenter study for safety. 
PK, 
and efficacy of 
hydromorphone HCl ER in an opioid tolerant pediatric population 7 to 17 years of age with chronic pain 
secondary to cancer and/or noncancer origins. 
Subjects with continuous. armmd-the-clock opioid treatment with at least 6 mg of daily hydromorphone 
(or other opioid equivalents) for 5 or more days (ie, opioid tolerant) will be evaluated for study 
qualification at screening (Visit 1). 
On the morning of Day 1 (Visit 2), qualified subjects will switch from their ctuTent therapy to receive the 
first dose of hydromorphone HCl ER at the clinic with a dose strength matching 66% of their prior opioid 
dosage based on the protocol-provided conversion table. Subjects will remain at the clinic for up to 24 
hours for safety and efficacy assessments and blood sampling. Subjects will continue to receive once 
daily hydromorphone HCl ER for 7 (± 2) days. No increase or decrease in hydromorphone HCl ER dose 
will be allowed. In the event of uncontrolled pain, 5 
mg of immediate release oxycodone can be used as 
rescue therapy at 1 to 2 tablets per dose up to 5 times per day depending on the strength of 
hydromorphone HCl ER received. 
Mallinckrodt Inc. 
Confidential and Proprietaiy 


Hyclromorphone HCl Extended-Release Tablets (Once Daily Hydromorphone) 
Protocol COV02520124 anco1porating Amendments l , 2, 3, and 4) 
Page 28 of78 
Subjects will return to the clinic on Day 7 (± 2 days) (Visit 3), take hydromorphone HCl ER in the 
morning, and stay for 12 hours while completing all remaining procedures and assessments before exiting 
the study (or proceeding to the optional safety extension). 
As safety assessments, vital signs and pulse oximet1y measurements will be conducted at scheduled visits 
and adverse events will be collected throughout the 7 (± 2) days of 
the treatment period. In 
addition, 
clinical laborato1y evaluations will be perfonned at Screening (Visit 1
) and study exit (Visit 3). 
Sparse blood sampling of 
a subset of subjects for the measurement of 
plasma hydromorphone and 
hydromorphone-3 -~ -D glucuronide metabolite concentrations will take place on Day 1 (Visit 2) at the 
following time points: predose, between 4 to 6 hours, 7 to 9 hours, 14 to 18 hours, and 22 to 24 hours 
postdose; and on Day 7 (± 2 days) (Visit 3) at the following time 
points: predose and between 8 to 12 
hours postdose. 
Pain intensity 
ratings will be recorded by subject on the electronic dia1y at Screening (Visit l)
; on Day 1 
(Visit 2) at the following time points: predose (within 15 minutes of initial dosing), and 1, 2, 4, 6, and 8 
hours (±15 minutes) postdose; on Days 2-6 (± 2) at the following time points: predose (within 15 minutes 
of dosing) and p1ior to bedtime; on Day 7 (± 2): predose (within 15 minutes of dosing). Age-appropriate 
pain scales will be used for the study, i.e. Faces Pain Scale-Revised (FPS-R) is for 7 to less than 12 
years and Visual Analog Scale (VAS) is for 12 to 17 years. 
A quality of 
life (PedsQL) questionnaire will also be completed on Day 1 (Visit 2) predose and at study 
exit/
Day 7 (Visit 3). 
Subjects who complete the 7 (± 2) days of 
treatment have the option to extend hydromorphone HCl ER 
usage for pain relief 
and safety observation for up to 3 additional weeks per investigator's discretion. 
Dose adjustment is allowed during this period. Subjects will visit the clinic weekly for continued 
eligibility assessment, safety evaluation, drng accountability (return and dispense), and/or dose 
adjustment. Subjects will visit the clinic at the end of safety observation extension for final assessment 
within 2 days after the last dose ofhydrommphone HCl ER. 
Subjects will be contacted by the site for a follow-up phone call at 7 (± 1) days after the study exit (Visit 
3) or the last dose of 
extended hydromorphone HCl ER usage. 
Inclusion Crite1ia: For inclusion into the study at screening (Visit 1), 
subjects must: 
1. Be adequately inf01med and understand the nature and 1isks of the sn1dy and must be able to provide 
a signature and date on the inf 
01med assent fo1m if 
appropliate, to pa1ticipate. Parent( s 
)/legal 
guardian must provide wlitten approval to participate. 
2. Be male or female subjects aged 7 to 17 years, inclusive. 
3. Be opioid-tolerant with chronic cancer or noncancer pain requiring continuous, around-the-clock oral 
or injectable opioid treatment. Opioid-tolerant is defined as having received a stable dose of 
regularly 
scheduled opioid or opioid combination products (including a regular rescue medication regimen) 
equivalent to least 6 mg of oral hydromorphone (see Table 15-1 for opioid dose conversion) per day 
for at least 5 days prior to first dose. 
4. (Female subjects of childbearing potential) Have a negative sernm pregnancy test result at screening 
and a negative urine pregnancy test result on Day 1 (Visit 2). Those subjects who are sexually active 
(as dete1mined by the investigator or designee) must be surgically sterilized (eg, hysterectomy or 
bilateral tubal ligation) at least 12 months plior to screening or use 1 of the following methods of 
bilth control at least 30 days p1ior to screening and for the duration of study paiticipation: hormonal 
contraception, intraute1ine contraceptive device, or spermicide with bani 
er method ( 
condolll, cervical 
cap, or diaphragm). Subjects should continue contraception for at least 30 days after the last dose of 
study drng. 
5. (Male subjects with reproductive potential who ai·e sexually active as dete1mined by the investigator 
or designee) Agree to use an acceptable method of contraception for the duration of 
the sn1dy 
(vasectomy or condom with spe1micide). 
6. Have established a favorable response to opioid therapy in reducing pain. 
Mallinckrodt Inc. 
Confidential and Proprietaiy 


Hydromorphone HCl Extended-Release Tablets (Once Daily Hydromorphone) 
Protocol COV02520124 anco1porating Amendments l , 2, 3, and 4) 
7. Require a minimum dose of 
4 mg (1 JURNISTA tablet) and a maximlllll dose of 16 mg 
Page 29 of78 
(1 hydrom01phone HCl ER tablet) after detennining 66% of 
the conve1ted dose ofhydromorphone 
HCl per day from an established conversion table (Table 15-1). 
8. Be able to swallow a whole tablet without breaking, cmshing, chewing or dissolving. 
9. Be expected to require extended opioid treatment for at least 1 week. 
10. Be able to communicate effectively with study personnel. 
11.  (Subjects and parents/legal guardian) Be able and willing to follow all protocol requirements and 
study restlictions. 
Exclusion Criteria: Subjects will be ineligible for the 
study if any of the following criteria are present: 
1. Have a life expectancy of less than 4 weeks. 
2. Have a histo1y of allergy or any significant intolerance with opioid treatment or allergies to sulfites as 
determined by the investigator or designee. 
3. Are cunently managed with opioid (ti·
anscutaneous) analgesic patches. 
4. Have a hist01y of diu g or alcohol dependence. 
5. Have a histo1y of renal, hepatic, cardiovascular, or respirat01y conditions that would contraindicate 
their paiticipation in this study as detennined by the investigator or designee. 
6. Plan to undergo a surgical procedure within 3 days of Day 1 and for the duration of paiticipation in 
the study. Subjects undergoing minor surgical procedures ( 
eg, central line inse1tion, biopsies) will be 
eligible for paiticipation in 
the study. 
7. Exhibit hemodynalnic instability as detennined by the investigator or designee. 
8. Have dysphagia or difficulty swallowing whole tablets as detennined by the investigator or designee. 
9. Have nairnwing of 
the digestive tract, often due to esophageal stiictures, Short Gut Syn&·ome, 
inflammat01y bowel disease, pelitonitis, cystic fibrosis, Meckel' s dive1ticulum, or past 
gastrointestinal surge1y. 
10. Have hypothyroidism, Addison's disease, asthma (including exercise induced asthma) requiring daily 
inhalers, an enlarged prostate, epilepsy, low blood pressure, seizure disorder, high intracranial 
pressure, gallbladder problems, pancreatic disease, liver disease, or kidney disease. 
11. Have an ileostomy or paralytic ileus. 
12. Have had a blood-product ti·ansfusion 
within 2 weeks plior to screening (Visit 1) or expected to 
require transfusion dming the study. 
13. Paiticipated in a study with any pain medication in the 2 weeks p1ior to screening (Visit 1). Subjects 
pa1ticipating in other investigational studies are allowed. 
14. Have a known histo1y ofhmnan immunodeficiency vims, hepatitis C vims or hepatitis B vims. 
Prior and Concomitant Treatment: 
Subjects will be allowed to continue taking any nonprohibited plior medication/therapy if: 
• The di11g was staited at least 14 days prior to first dose of 
study diug, AND 
• The dose of 
medication is expected to remain unchanged for the duration of 
study pa1ticipation. 
Pe1tinent infonnation for any medication taken dming 
the study will be recorded. 
Investigational Product and Administration: 
• EXALGO (Hydi·
omorphone HCl ER) 8-mg, 12-mg, and 16-mg tablets. 
• JURNISTA (hydromorphone HCl ER) 4-mg tablets. 
Tablets to be swallowed whole and not broken, chewed, dissolved, or cmshed. 
Rescue Medication: 
• Immediate-release oxycodone (5 mg tablets). 
Mallinckrodt Inc. 
Confidential and Proprietaiy 


Hydromorphone HCl Extended-Release Tablets (Once Daily Hydromorphone) 
Protocol COV02520124 anco1porating Amendments l , 2, 3, and 4) 
Safety Assessment: 
1. Physical examination. 
2. Clinical laborat01y tests. 
3. Vital sign measurements. 
4. Pulse oximetty measurements. 
5. AEs. 
Assessments: 
1. The effectiveness endpoint is pain intensity measured on a FPS-R or VAS. 
2. The health outcomes endpoint is quality of life, as measured by the PedsQL. 
Pharmacokinetics: 
Page 30 of78 
Blood samples for the dete1mination of 
plasma hydrommphone and hydromorphone-3-13-D glucuronide 
metabolite concentt·
ations will be collected in selected windows of time: predose, 4 to 6 hours, 7 to 
9 hours, 14 to 18 hours, 22 to 24 hours postdose on Day 1 (Visit 2); and predose and 8 to 12 hours 
postdose on Day 7 ± 2 (Visit 3) in 
a subset of 
subjects. 
Statistical Considerations: 
Analysis Populations 
The analysis populations include the 
following: 
• The Safety Population will include all subjects who receive any quantity of study diug. 
• The PK Population will consist of all subjects who receive at least 1 dose of sn1dy di11g and have 
any samples collected after dosing at Visit 2 and/or Visit 3 that were analyzed for hydi·ocodone 
and hydi·ommphone-3-
13-D glucuronide. 
• The Modified Intent-To-Treat Population will consist of all subjects who receive sn1dy diu g and 
who have at least 1 postdose pain intensity assessment. 
Subject Characteristics 
Demographic and baseline characteristics (including age, sex, race, ethnicity, weight, height, and medical 
histo1y) will be summalized for the safety population by descliptive statistics. No statistical analyses will 
be perfonned. 
Effectiveness and Health Outcomes Analysis 
The endpoints below will be summa1ized at each assessment time point: 
• Pain intensity with validated pain intensity scales FPS-Rand VAS. 
• Quality of life, as measured by the PedsQL. 
Phaimacokinetic Analysis 
A population PK dataset will be developed from the pooled pediattic and adult data from sn1dies C-2005-
013-01, C-2005-032-02 and 42801-PAI-1009 and the cmTent study. Population PK analyses will be 
conducted via nonlinear mixed effect modeling using the nonlineai· mixed-effects modeling software 
NONMEM®, Version 7 or higher (ICON Development Solutions, Hanover, MD). A covaliate analysis 
will be unde11aken to detennine the contribution of demographic and disease characteristics to variability 
in 
hydromorphone PK. Individual predicted hydromorphone exposure metlics ( 
appai·
ent first-order 
terminal elilnination rate constant, the apparent plasma tenninal elilnination half-life, the lninimlllll 
plasma concentt·ation at steady-state, the peak plasma concentt·ation at steady-state, the average 
concentt·ation at steady-state, and the ai·
ea under the plasma time-concentration curve at steady-state) will 
be de1ived from estimated parameters from the final model. 
Safety Analysis 
Data listings will be provided for all protocol-specified safety data. The Medical Dictionaiy for 
Regulat01y Activities (MedDRA Version 9.1 or higher) will be used to classify all AEs with respect to 
system organ class and prefeITed te1m. Numbers of subjects with tt·eatment-emergent AEs will be 
summa1ized. 
Mallinckrodt Inc. 
Confidential and Proprietaiy 


Hyclromorphone HCl Extended-Release Tablets (Once Daily Hydromorphone) 
Protocol COV02520124 anco1porating Amendments l , 2, 3, and 4) 
Page 31 of78 
For vital signs and pulse oximet1y, descriptive statistics will be provided at each scheduled time point, 
including study exit. Descriptive statistics will be provided on changes from baseline of 
these assessments 
at each scheduled time point after baseline. No formal statistical tests will be perfonned. 
Ethical Considerations: The study will be conducted in 
compliance with applicable US Food and Drng 
Administration (FDA) regulations, International Council for Haimonisation (ICH) guidelines for Good 
Clinical Practice (GCP), and in accordance with generally accepted ethical principles for the conduct of 
human research such as the Declaration of Helsinki. 
The institutional review board (IRB) must review and approve the protocol and info1med assent/consent 
forms before any subjects are emolled. Before any protocol-required procedures are perfo1med, the 
subject must be able to provide a signature and date on the info1med assent fo1m (IAF), if 
appropriate, to 
paiticipate. The subject's legal guardian or pai·
ent(s) must provide written approval to pa1ticipate. 
Mallinckrodt Inc. 
Confidential and Proprietary