Clinical trial NCT01709721
Conditions: Management of Chronic Pain
Keywords: Hydromorphone Hydromorphone Hydrochloride Pain Management Non-narcotic analgesics
Sponsor: Piramal Critical Care, Ltd.
Start date: 2013-02-01; Completion date: 2018-02-01
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety and efficacy of hydromorphone hydrochloride by intrathecal administration using a programmable implantable pump.

Detailed description:
A Controlled, Two-Arm, Parallel Group, Randomized Withdrawal Study to Assess the Safety and Efficacy of Hydromorphone Hydrochloride Delivered by Intrathecal Administration Using a Programmable Implantable Pump

Arms: arm 1: Subjects on hydromorphone hydrochloride for the duration of therapy. arm 2: Subjects on hydromorphone hydrochloride titrated downward
Interventions: intervention 1: Hydromorphone Hydrochloride intervention 2: Programmable Implantable pump
Intervention descriptions: intervention 1: Opioid for chronic pain intervention 2: Programmable Implantable pump delivering intrathecal hydromorphone

Protocol documents:
Prot_000.pdf: 
Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
1
CONFIDENTIAL
MALLINCKRODT PHARMACEUTICALS, INC
INVESTIGATIONAL NEW DRUG PROTOCOL
INTRATHECAL HYDROMORPHONE HCL 10 MG/ML
PROTOCOL NUMBER CNS-HYD201US
VERSION 5.0 DATED 01 AUGUST 2016
AMENDMENT REVISING PRIOR VERSION 4.0 DATED 24 JUNE 2016
A Controlled, Two-Arm, Parallel Group, Randomized Withdrawal Study 
To Assess The Safety And Efficacy Of Hydromorphone Hydrochloride 
Delivered By Intrathecal Administration Using A Programmable 
Implantable Pump
SPONSOR:
MALLINCKRODT PHARMACEUTICALS INC
675 MCDONNELL BLVD
HAZELWOOD, MO 63042
USA
CONFIDENTIAL


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
2
CONFIDENTIAL
SUMMARY OF CHANGES FROM VERSION 4.0 TO VERSION 5.0
DATED 01 AUGUST 2016
This protocol amendment was required (1) to correctly specify a dose titration up to 
10 mg/day rather than 5 mg/day and (2) to further clarify the handling of subjects who are 
dropped or otherwise go off study prior to the 5-week randomized withdrawal period. 
These and other changes are listed below:
1. Version is changed from v4.0 to v5.0 and protocol re-dated as appropriate. Title page, 
headers and footers are revised appropriately.
2. The Protocol Synopsis, Dosage & Regimen Section was corrected to specify a 0.1 mg/day 
to 10 mg/day dosage based on dose titration, rather than 0.1 mg/day to 5 mg/day.
3. The Protocol Synopsis, Study Visit Schedule Section, last paragraph, was revised to include 
those subjects who go off study prior to randomization, since the protocol defines 
treatment failures as those subjects who fail after randomization.
4. Section 1.3.3, 4th paragraph, was corrected to specify dose titration up to 10 mg/day rather 
than 5 mg/day.
5. Section 1.4 Study Rationale, final paragraph, is revised to include those subjects who do not 
enter the 5-week randomized withdrawal period.
6. Section 3.1, Description of Trial Design, third paragraph on pg 34, is revised to add text 
concerning those subjects who were dropped prior to randomization. These subjects will 
complete the study visit that they are on, go directly into CNS-HYD202US and complete 
scales there at the Screening and Baseline Visit, since they will not have a Day 119 or 
treatment failure visit that will carry over.
7. Section 3.5.1.2, 12-Week Open-Label Treatment Phase, last paragraph, was revised to 
clarify the situation of subjects discontinuing prior to randomization and not rolling over
into the CNS-HYD202US trial.
8. Appendix Table A-2, footnote ‘e’ is revised to include subjects who are dropped prior to 
randomization.
9. Minor edits were made as necessary to correct spelling, capitalization, grammar or format 
errors.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
3
CONFIDENTIAL
Table of Contents
LIST OF IN-TEXT TABLES................................................................................................. 6
LIST OF APPENDICES........................................................................................................ 6
LIST OF ABBREVIATIONS ................................................................................................ 7
1.0
INTRODUCTION..................................................................................................... 18
1.1
Background ........................................................................................................... 18
1.2
Nonclinical Assessments........................................................................................ 19
1.2.1
Pharmacology................................................................................................. 19
1.2.2
Toxicology ..................................................................................................... 20
1.3
Clinical Experience................................................................................................ 21
1.3.1
Overview of Clinical Pharmacology ............................................................... 21
1.3.2
Overview of Clinical Pharmacology ............................................................... 22
1.3.3
Overview of Efficacy and Safety .................................................................... 24
1.4
Study Rationale ..................................................................................................... 27
2.0
PURPOSE AND STUDY OBJECTIVES.................................................................. 29
2.1
Purpose.................................................................................................................. 29
2.2
Study Objectives.................................................................................................... 30
2.2.1
Primary Objective........................................................................................... 30
2.2.2
Secondary Objective....................................................................................... 30
3.0
STUDY DESIGN...................................................................................................... 30
3.1
Description of Trial Design.................................................................................... 30
3.2
Study Endpoints..................................................................................................... 34
3.2.1
Primary Endpoint............................................................................................ 34
3.2.2
Secondary Endpoints ...................................................................................... 34
3.3
Diagnosis of Granuloma ........................................................................................ 35
3.3.1
Treatment of Granuloma................................................................................. 35
3.4
Measures to Minimize Bias.................................................................................... 36
3.4.1
Blinding.......................................................................................................... 36
3.4.2
Randomization/Assignment to Study Drug ..................................................... 36
3.5
Study Drugs........................................................................................................... 37
3.5.1
Rationale for Doses and Dosing Regimen ....................................................... 37
3.5.2
Dose Interruption............................................................................................ 40


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
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CONFIDENTIAL
3.6
Concomitant Medications ...................................................................................... 40
3.6.1
Prior and Concomitant Medications ................................................................ 40
3.6.2
Prohibited Concomitant Medications .............................................................. 41
3.7
Nonpharmacologic Interventions ........................................................................... 41
3.8
Duration of Therapy............................................................................................... 41
3.9
Procedures for Monitoring Subject Compliance ..................................................... 41
4.0
STUDY POPULATION............................................................................................ 42
4.1
Inclusion Criteria ................................................................................................... 42
4.2
Exclusion Criteria .................................................................................................. 42
5.0
SAFETY ASSESSMENTS ....................................................................................... 43
5.1
Collection of Adverse Events Data......................................................................... 43
5.2
Physical Examinations and Medical History .......................................................... 44
5.2.1
Complete Physical Examination...................................................................... 44
5.2.2
Medical History, Pump Implantation and Surgical History.............................. 44
5.3
Clinical Laboratory Testing and ECGs................................................................... 44
5.4
Vital Signs............................................................................................................. 45
5.5
Documentation of Concomitant Medications ......................................................... 45
6.0
PHARMACOKINETICS .......................................................................................... 45
7.0
PHARMACODYNAMICS ....................................................................................... 45
8.0
EFFICACY............................................................................................................... 45
9.0
STUDY VISITS........................................................................................................ 46
9.1
Screening............................................................................................................... 46
9.2
Baseline Evaluations.............................................................................................. 47
9.3
Dose Conversion and Optional Titration Period ..................................................... 47
9.4
Continuous Dosing Period (Day 1 to Day 83) ........................................................ 48
9.5
Randomized Withdrawal and Efficacy Evaluation Period (Day 84 to Day 119)...... 49
9.6
Long-Term Follow Up (CNS-HYD202US Safety)................................................. 50
9.7
Final Visit.............................................................................................................. 51
10.0
PREMATURE DISCONTINUATION FROM STUDY ............................................ 51
11.0
PREMATURE DISCONTINUATION FROM STUDY DRUG ................................ 51
12.0
PRODUCT SPECIFICATIONS ................................................................................ 52
12.1
Description......................................................................................................... 52
12.2
Formulation, Packaging, and Labeling................................................................ 52


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
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CONFIDENTIAL
12.3
Receipt, Storage and Stability of Hydromorphone Intrathecal............................. 52
12.4
Preparation and Administration of Study Drug ................................................... 52
12.5
Ordering and Distribution of Study Drug............................................................ 53
12.6
Accountability of Study Drugs ........................................................................... 53
13.0
SAFETY MONITORING AND ADVERSE EVENTS.............................................. 53
13.1
Adverse Events .................................................................................................. 53
13.2
Serious Adverse Events...................................................................................... 56
13.2.1
Reporting Requirements for Serious Adverse Events ...................................... 57
13.2.2
Recording of Serious Adverse Events ............................................................. 58
14.0
STATISTICAL CONSIDERATIONS....................................................................... 58
14.1
Sample Size Determination ................................................................................ 58
14.2
Analysis Data Sets.............................................................................................. 59
14.3
Primary Efficacy Analysis.................................................................................. 59
14.4
Secondary Analyses ........................................................................................... 60
14.5
Safety................................................................................................................. 60
15.0
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE....... 60
15.1
Data Collection and Reporting............................................................................ 60
15.2
Study Monitoring ............................................................................................... 61
15.3
Data Disclosure and Subject Confidentiality....................................................... 61
16.0
PROTECTION OF HUMAN SUBJECTS................................................................. 62
16.1
Declaration of Helsinki....................................................................................... 62
16.2
Institutional Review Board/Ethics Committee .................................................... 62
17.0
REFERENCE LIST................................................................................................... 63
18.0
SPONSOR SIGNATURE.......................................................................................... 81


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
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CONFIDENTIAL
LIST OF IN-TEXT TABLES
Table 13-1
Causality Categories for AE Descriptions ....................................................... 55
Table 13–2
Severity Assessment Terminology for Reporting Adverse Events 
(CTCAE v4.03) ................................................................................................................... 56
Table 13–3
Reporting Requirements for Adverse Events................................................... 58
Table 13–4
Contact Information for SAE Reporting.......................................................... 58
Table A- 1: Schedule of Study Procedures: Screening and Chronic Dosing Phase to Day 56 68
Table A- 2: Schedule of Study Procedures: Final 7 Days of Continuous Dosing, Randomized 
Withdrawal and Efficacy Evaluation Period......................................................................... 70
LIST OF APPENDICES
Appendix A: Schedule of Study Procedures......................................................................... 68
Appendix B: National Cancer Institute Common Terminology Criteria for Adverse Events . 72
Appendix C: Visual Analog Scale of Pain Intensity (VASPI)............................................... 73
Appendix D: Clinical Opiate Withdrawal Scale (COWS)..................................................... 74
Appendix E: Subjective Opiate Withdrawal Scale (SOWS).................................................. 75
Appendix F: Brief Pain Inventory (BPI)............................................................................... 77
Appendix G: Patient Global Impression of Change (PGIC).................................................. 79
Appendix H: Short-Form McGill Pain Questionnaire (SF-MPQ).......................................... 80


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
7
CONFIDENTIAL
LIST OF ABBREVIATIONS
ABBREVIATION
DEFINITION
AE
Adverse event
CFR
Code of Federal Regulations
CMP
Comprehensive Metabolic Panel
cGMP
Current Good Manufacturing Practices
CSF
Cerebral Spinal Fluid
CNS
Central nervous system
COWS
Clinical Opiate Withdrawal Scale
CRF
Case report form
CRU
Clinical research unit
CTCAE
Common Terminology Criteria for Adverse Events (v. 4.03)
EC
Ethics Committee
EDC
Electronic Data Capture
FDA
Food and Drug Administration
g
Gram
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice(s)
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IRB
Institutional Review Board
IT
Intrathecal Injection
ITT
Intent-To-Treat
IP
Investigational Product
kg
Kilogram
L
Liter
MedDRA
Medical Dictionary for Regulatory Activities
mcg
Microgram


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
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CONFIDENTIAL
ABBREVIATION
DEFINITION
MFD
Maximum Feasible Dose
mg
Milligram
mL
Milliliter
MNK
Mallinckrodt Pharmaceuticals Inc
MRI
Magnetic Resonance Imaging 
NCI
National Cancer Institute
NDA
New Drug Application
PGIC
Patient’s Global Impression of Change
PI
Principal Investigator
PTM
Personal Therapy Manager
SAE
Serious Adverse Event 
SOWS
Subjective Opioid Withdrawal Scale
U.S.
United States (of America)
USP
United States Pharmacopeia
VASPI
Visual Analog Scale of Pain Intensity
WHODD
World Health Organization Drug Dictionary


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
9
CONFIDENTIAL
INVESTIGATOR STATEMENT
I have read and understand the protocol and agree to implement the study in accordance with 
the procedures set forth in the protocol and in accordance with the sponsor's guidelines, all 
applicable government regulations, and the International Conference on Harmonization Good 
Clinical Practice Guidelines E6 (ICH-GCP).
I will maintain accurate source documents from which data are transcribed onto case report 
forms and accurate drug accountability records that show the receipt and disposition of all 
study drugs.
I will provide adequate protocol training to my associates, colleagues, and employees 
assisting in the conduct of the study. 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and informed consent form prior to enrollment of subjects in the study. I understand that any 
modifications to the protocol made during the course of the study must first be approved by 
the IRB/EC prior to implementation except when such modification is made to remove an 
immediate hazard to the subject.
I will ensure that a fully executed IRB-approved informed consent form is obtained from each 
subject prior to initiation of any study procedures. 
I will report (within 24 hours) any serious adverse event, regardless of relationship to study 
drug, or pregnancy that occurs during the course of the study, in accordance with the 
procedures described in Section 13.2 of the protocol. I will notify the sponsor if I become 
aware that a partner of a study subject becomes pregnant while the subject was receiving this 
study drug.
I will submit all protocol inclusion/exclusion violations to the medical monitor for approval 
prior to enrollment of the subject in the study.
I will allow the sponsor, Mallinckrodt Pharmaceuticals, Inc. and its agents, as well as the 
United States (U.S.) Food and Drug Administration (FDA) and other regulatory agencies to 
inspect study facilities and pertinent records at reasonable times and in a reasonable manner, 
ensuring subject confidentiality. If I am notified that this study is to be inspected by a 
regulatory agency, I will notify the sponsor as soon as possible thereafter (no later than 
1 week).
This protocol contains information that is proprietary to Mallinckrodt Pharmaceuticals, Inc. 
The information contained herein is provided for the purpose of conducting a clinical trial for 
Mallinckrodt Pharmaceuticals, Inc.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
10
CONFIDENTIAL
The contents of this protocol may be disclosed to study personnel under your supervision and 
to your IRB/EC. The contents of this protocol may not be disclosed to any other parties 
(unless such disclosure is required by government regulations or laws) without the prior 
written approval of Mallinckrodt Pharmaceuticals, Inc.
__________________________________________
_______________________
Investigator’s Signature
Date
__________________________________________
Investigator’s Print Name


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
11
CONFIDENTIAL
PROTOCOL SYNOPSIS (PAGE 1 of 7)
Study Title
A Controlled, Two-Arm, Parallel Group, Randomized Withdrawal Study to Assess the Safety and 
Efficacy of Hydromorphone Hydrochloride Delivered by Intrathecal Administration Using a
Programmable Implantable Pump (CNS-HYD201US)
Sites
10 to 30
Indication
Preservative free hydromorphone hydrochloride injection for intrathecal use is indicated for the 
management of pain not responsive to non-narcotic analgesics. Hydromorphone hydrochloride 
administered intrathecally, provides pain relief for extended periods without attendant loss of motor, 
sensory or sympathetic function.
Objectives
Primary objective: 
The primary objective of this clinical trial is to demonstrate the superiority of intrathecal hydromorphone 
hydrochloride in subjects who are on an optimal dose compared with those who have their dose titrated 
downward during the randomized withdrawal period as measured by treatment failure rate. 
Secondary objective:
To evaluate the safety of hydromorphone hydrochloride given by the intrathecal route of administration.
Study 
Design
This is a controlled, prospective, randomized withdrawal trial to be conducted at 10 to 30 US clinical 
trial sites that are experienced with the use of intrathecal opioids. All subjects will be entered after 
signing an IRB approved informed consent. Subjects who currently have a SynchroMed® II Implantable 
Infusion Pump will be eligible to enroll in this trial. For subjects that do not have a current infusion 
pump implanted, they may be consented and enrolled only after pump implantation and stabilization on
intrathecal morphine. Subjects who are naïve to intrathecal therapy, may be enrolled 2-weeks after pump 
implantation with a SynchroMed® II Implantable Infusion Pump. Subjects entering the study should 
have a reasonable likelihood of benefiting from intrathecal treatment with an opioid such as 
hydromorphone hydrochloride.
Subjects entering the trial on a stable dose of intrathecal hydromorphone hydrochloride may be 
converted directly to study medication without dose adjustment.
Subjects converted from their current intrathecal morphine therapy to intrathecal hydromorphone 
hydrochloride will be dosed according to the following scheme:
Subject Status on Morphine
Conversion Ratio
Dose ≤ 30 mg IT morphine and tolerating therapy well
1 : 6 1
Dose > 30 mg IT morphine or subject has significant 
side effects on morphine
1 : 12 2
1Conversion is based on mg-morphine equivalence such that for each 6 mg morphine sulfate the dose is converted to 1 
mg hydromorphone hydrochloride.
2 Conversion is based on mg-morphine equivalence such that for each 12 mg morphine sulfate the dose is converted to 1 
mg hydromorphone hydrochloride.
The conversion will take place by removing the current product in the pump and then replacing the 
contents with hydromorphone hydrochloride Intrathecal injection . At the discretion of the investigator 
the pump reservoir may be rinsed with preservative free sterile saline or the study medication 
(hydromorphone hydrochloride for intrathecal injection). The subject should be contacted by telephone 
24 hours after initiating study medication. If combinations were used in the previous intrathecal therapy, 
oral medications permitted by the protocol may be provided to replace the intrathecal combination 
regimen. However, for the duration of the CNS-HYD201US trial only hydromorphone hydrochloride 
may be used in the intrathecal pump as monotherapy. Depending on the subjects starting dose on 
hydromorphone hydrochloride, either a 2 mg/mL or 10 mg/mL formulation of hydromorphone 
hydrochloride for intrathecal injection may be used. Dosing with the SynchroMed II Implantable 


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
12
CONFIDENTIAL
PROTOCOL SYNOPSIS (PAGE 2 of 7)
Study 
Design 
(Cont.)
Infusion pump may utilize simple continuous, complex continuous with or without Personal Therapy 
Manager (PTM) dosing.
Subjects who are converted directly to a therapeutic dose of hydromorphone hydrochloride based on a 
1:6 conversion morphine equivalent dose of their current opioid should start the study on Day 1 
(see Appendix A: Schedule of Study Procedures). For subjects that are converted to a lower dose based 
on the 1:12 conversion scheme for safety reasons, up to five (5) optional study visits (Days A, B, C, D 
and E) are permitted to allow dose titration to a therapeutic dose that is well tolerated. These optional 
visit days may be from three (3) to seven (7) days apart. After the subject achieves a therapeutic dose of 
hydromorphone hydrochloride the procedures starting with Day 1 of the study will be followed to 
ensure the subject is treated for the full 12 week period at a therapeutic dose of intrathecal 
hydromorphone hydrochloride.
Dose adjustments thereafter will be allowed by adjusting the pump speed, with a maximum dose 
adjustment of no more than 50% if the current dose is 0.5 mg or less, and 25% for subjects on doses 
above 0.5 mg, as described in the following scheme:
Dose of Hydromorphone 
Hydrochloride IT
Maximum Dose 
Adjustment
0.1 to 0.5 mg/day
50%
> 0.5 mg/day
25%
A maximum dose of 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any time 
during this study. For PTM dosing this maximum dose includes the subjects activated doses that are 
allowed by the device programming.
Subjects may be given oral supplemental medication for pain up to a maximum of 180 mg-equivalent 
morphine per day prior to Day 77 of treatment, however, the objective of the trial during this period is to 
achieve an optimal dose of intrathecal hydromorphone hydrochloride and eliminate any oral 
supplement. Oral supplement in excess of 180 mg-equivalent morphine per day or other interventions 
due to intolerable pain, is not permitted and the subject will be withdrawn from the trial and weaned off 
intrathecal hydromorphone hydrochloride and converted to other appropriate pain therapies. From Day 
77 to Day 119 or rescue, subjects are permitted up to 60 mg-equivalent morphine per day only to 
manage possible withdrawal symptoms.
On Day 77 the pump should be refilled with intrathecal hydromorphone hydrochloride and any final 
adjustments made to the daily dose or programming. On Day 77, the subject will be given a remote 
monitoring device to measure VASPI scores twice daily in the morning beginning (5:30 am to 12:00 
noon) and in the evening (6:00 pm to 11:45 pm). After Day 77 and during the randomized double-blind 
period there should be no dose adjustments to intrathecal hydromorphone hydrochloride other than 
those dictated by the protocol for subjects on the control arm who have their dose titrated downward.
After Day 77, there should also be no changes to the pump programming for simple continuous, 
complex continuous or PTM dosing regimens until after the completion of the trial.
At the end of the 12 week continuous dosing period, subjects who meet criteria for randomization will 
be randomized in a 1:1 ratio to either remain at their current dose of hydromorphone hydrochloride or 
who have their dose titrated downward (control group) in a blinded fashion. The criteria for 
randomization is defined as an average VASPI score of 50 mm or less on a scale of 100 mm for the last 
5 days with daily pain measurements prior to randomization on Day 84. After Day 77 the subject should 
be off any oral supplement of opioid or other prescription medications for pain prior to randomization.
For those subjects randomized to be withdrawn from therapy with hydromorphone hydrochloride on 
Day 84, the pump speed will be adjusted to decrease the total daily dose each 7 days (± 1 day), starting 
at a dose of 75%, 50%, 25%, 12.5% and approximately 0% of the dose at the time of randomization. For 
PTM dosing, the base continuous dose and the PTM dose would be decreased by the specified 
percentages above. The total maximum dose of 10 mg/day will be the combined total of the decreased 
base continuous dose and PTM dose.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
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PROTOCOL SYNOPSIS (PAGE 3 of 7)
Study 
Design 
(Cont.)
For those subjects randomized to stay on their current dose of hydromorphone hydrochloride, they will 
also return to the clinic on the same schedule for assessments and for mock pump adjustments. The
blind will be maintained by having an independent unblinded medical professional at the site to manage 
the pump infusion rate and medication provided to the subject. 
Pain assessments using the VASPI scale will continue twice daily (morning and evening) from Day 77 
prior to the randomization period and throughout the randomized withdrawal period. COWS and SOWS 
assessments will be performed at specified time points to assess any withdrawal symptoms. Subjects 
will be permitted a maximum of 60 mg of morphine-equivalent oral opioid per day during the 
randomized withdrawal period only for the purpose of managing withdrawal symptoms. This oral 
supplement is not intended to manage pain and should be provided only if the subject starts to 
experience withdrawal symptoms. No other changes to prescription pain medications or non-
pharmacologic interventions being used to help manage pain are allowed from Day 84 to 119, or 
treatment failure. Baseline pain for the double-blind randomized withdraw period is defined as the 
average of the last 5 days in the last 7 days with daily pain measurements while on the optimal 
intrathecal dose of hydromorphone hydrochloride, between Days 77 to 83 of the open-label dosing 
period.
Treatment Failure Criteria: After randomization, a treatment failure will be defined by the following 
criteria:
1.
A subject who experiences an increase of 20 mm or more above the baseline value on a 100
mm VASPI based on the average of 5 days, or
2.
A subject who experiences intolerable pain that in the opinion of the investigator requires 
intervention (ie, rescue), or
3.
Any subject who has other interventions for pain that violate the protocol from Day 84 to 119,
including:
a. Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent to manage 
withdrawal symptoms, or
b. Has a change in non-opioid oral prescription medications or non-pharmacological 
treatments being administered for the management of pain.
Note: A subject who does not have sufficient data for evaluation, drops out for any other reasons
that are not listed above, or who experiences withdrawal syndrome as identified by COWS > 12 
during the double-blind treatment phase will not be classified as a treatment failure in the primary 
efficacy analysis.
Prior to rescue medication being administered, subjects will complete Day 119 study assessments, if 
possible. After confirming with the investigator that it is acceptable to take rescue medication, if a 
subject cannot return to the study site for assessments they will be instructed to complete a VASPI score 
on the remote monitoring device immediately prior to taking oral rescue medication. If the subject can 
return to the site, rescue may be performed by either oral or IV medication being administered or by 
increasing the pump speed to achieve a therapeutic dose of hydromorphone hydrochloride, or both.
Subjects will be evaluated for side effects and clinical complications associated with the use of 
intrathecal hydromorphone hydrochloride. Signs and symptoms of an inflammatory granuloma, 
including radicular pain, loss of drug efficacy, and spinal cord compression will be monitored by 
clinical assessments. If there are clinical signs or symptoms identified which may indicate an 
inflammatory mass formation, an MRI with or without contrast or CT myelogram will be performed to 
evaluate the potential presence of an inflammatory granuloma as opposed to other catheter related 
problems that may result in reduced delivery or clinical symptoms. Events that may be related to an 
inflammatory granuloma will be classified as a confirmed granuloma, suspected granuloma, other 


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD201US
Intrathecal Hydromorphone
Version: 5.0
01 August 2016
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PROTOCOL SYNOPSIS (PAGE 4 of 7)
Study 
Design 
(Cont.)
catheter related problem (confirmed not caused by a granuloma) or other clinical event caused by the 
underlying disease or other non-catheter/product related event.
Following the 5-week randomized withdrawal period, all randomized subjects may be allowed to 
continue on intrathecal hydromorphone hydrochloride for up to 12 months of safety evaluation by 
entering the open-label safety study (CNS-HYD202US) if the investigator believes that the subject 
meets the study selection criteria for the study and would benefit from participation in the study.
Subjects in the control group who had their dose titrated down will be first titrated back onto intrathecal 
hydromorphone hydrochloride as part of the CNS-HYD202US protocol.
A subject who is a treatment failure or is dropped from the study prior to randomization can enroll into 
the long term safety study (CNS-HYD202US) if the subject meets the study selection criteria for 
CNS-HYD202US and would benefit from study participation. Subjects who experience a drug related 
adverse event that requires discontinuation after randomization will not be qualified for the long-term 
extension study, CNS-HYD202US. Subjects will be followed for safety for the duration of their 
treatment with intrathecal hydromorphone hydrochloride using the SynchroMed® II Programmable 
Pump or until the study completion.
Dosage &
Regimen
0.1 mg/day to 10 mg/day based on dose titration.
Sample size
Approximately 80 randomized (40 per arm).
Study 
population
Subjects requiring intrathecal opioid treatment to manage chronic intractable pain, age 18 to 75 years of 
age.
Main 
Inclusion 
Criteria
Subjects must meet all of the following criteria to be included:
1.
Subject must be at least 18 years of age and no more than 75 years old.
2.
Clinically diagnosed with chronic pain for at least a 6-month period.
3.
Subject is presently on intrathecal pain medication and has a SynchroMed II Implantable pump or 
meets clinical criteria for implantation of a SynchroMed II Implantable pump. Subjects who are 
naïve to intrathecal therapy, may be enrolled 2-weeks after pump implantation.
4.
Subject agrees to sign a Pain Treatment Agreement (Narcotic Contract) limiting narcotic 
prescriptions to the study physician.
5.
Subject must be cognitively intact and, in the opinion of the investigator, capable of participation in 
the trial.
6.
Female subjects of child-bearing potential must agree to use a medically acceptable and effective 
double-barrier method of birth control.
7.
Subjects with existing SynchroMed II Implantable pumps and are reasonably expected to benefit 
from intrathecal opioid therapy only.
8.
Subjects who are capable of receiving an MRI with or without contrast or CT myelogram, if 
required by the study protocol.
9.
Provides written Ethics Committee approved informed consent.
10. Willing to comply with all study procedures and requirements.


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PROTOCOL SYNOPSIS (PAGE 5 of 7)
Main 
Exclusion 
Criteria
Subjects meeting any of the following criteria will be excluded:
1.
Women who are pregnant or are breast-feeding.
2.
Subjects who have participated in an investigational drug or device trial within 4 weeks prior to 
enrollment.
3.
Subject has any known or suspected allergy to hydromorphone or to the materials of the infusion 
pump or intrathecal catheter.
4.
Subject is scheduled for a pump or catheter replacement within 6 months of their enrollment into 
the trial.
5.
Subject has a history of dependence and abuse of opioids, stimulants, alcohol, or benzodiazepines, 
as defined by DSM-IV criteria, within the past year (physical dependence on prescribed opioid 
analgesics is allowed but abuse of opioids according to DSM-IV is not permitted, ie, opioid 
addiction for recreational use).
6.
Subjects who show signs of active systemic infection.
7.
Subjects with a metastatic cancer to the spinal canal or a known central nervous system 
contraindication to intrathecal therapy.
8.
Subject has a condition requiring diathermy procedures.
9.
Subject has a life expectancy of less than 12 months.
10. Subject cannot independently comprehend and participate in the required assessments, including 
responding to the VASPI, SF-MPQ, COWS, SOWS, BPI and PGIC measurement tools.
11. Subject is not considered to be medically or psychologically appropriate for pump implantation.
12. Subjects who are unable or unwilling to return to all of the required follow-up visits.
13. Subjects with active implanted devices such as pacemakers, defibrillators, and cochlear implants or 
other medical device use, if in the opinion of the investigator the device would interfere with the 
ability to perform an MRI or CT myelogram.
14. As a result of medical review and physical examination, the Investigator considers the subject unfit 
for the study.
15. Pain located above the shoulders in the head or neck region (e.g. trigeminal neuralgia), central pain 
syndromes or any other condition in which it is judged to be unlikely that the subject would benefit 
from intrathecal administration of the drug product.
16. Subjects who have previously been unresponsive to intrathecal hydromorphone therapy.
Study Visit 
Schedule
(See 
Appendix 
A: Schedule 
of Study 
Procedures)
Subjects will be screened and evaluated for study participation prior to administration of any study 
medications. Screening, baseline and subject initiation on study medication (Day 1 or optional titration 
day) may be conducted on a single day. After signing an informed consent, and confirming eligibility 
and conformance with all entry criteria, the subject will be enrolled in the trial. Subjects will have
hydromorphone hydrochloride 2 mg/mL or 10 mg/mL for injection loaded into the intrathecal pump and 
either start directly at Day 1 of the study if at a therapeutic dose, or will be titrated to a therapeutic dose.
Subjects who require titration will return to the clinic up to two times a week (each 3 to 7 days) for up to 
4 weeks to have dose adjustments. The subject will continue dose adjustments to a stable dose and then 
remain on treatment for the chronic dosing period. Once at a stable dose, subjects will start Day 1 of the 
study according to the Schedule of Study Procedures (Appendix A). Dose adjustments during Days 1 to 
77 are permitted as needed to optimize the therapy. A final dose adjustment may be conducted on Day 
77, after which no pump programming changes or dose adjustments are permitted other than those 
dictated by the protocol for subjects randomized to the control arm who have their dose titrated 
downward as part of the randomized withdraw design. 
Subjects stabilized on intrathecal hydromorphone hydrochloride and who meet the randomization 
criteria, will be randomized to remain at their current IT dose or to have their dose titrated downward 
over a four week period. Subjects will be monitored by the physician and examined at least every week 


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over a 5-week period for any indications of complications with the device or clinical signs.
PROTOCOL SYNOPSIS (PAGE 6 of 7)
Study Visit 
Schedule
(See 
Appendix 
A: Schedule 
of Study 
Procedures)
Symptoms of concern, and other study procedures. Subjects will record a VASPI score twice daily at 
approximately the same times each day, once in the morning (between 5:30 am and 12:00 noon) and 
once in the evening (between 6:00 pm and 11:45 pm).
Subjects who complete the study or rescue due to treatment failure during the randomized withdrawal 
period or were dropped from the study prior to randomization will be allowed to enter the 
CNS-HYD202US trial and receive intrathecal hydromorphone hydrochloride treatment for 12 months 
for ongoing safety evaluations.
Study 
Duration
It is planned that each subject will participate in the study for up to 24 weeks as part of this protocol
with an extension for up to 12 additional months permitted at the discretion of the subject and attending 
physician if entered into the CNS-HYD202US long term safety trial. 
Safety 
Analysis
Clinical signs and symptoms that may indicate an inflammatory granuloma include:

A sudden decrease in therapeutic response requiring increased daily doses that is not attributed 
to other assignable causes (e.g. mechanical failures, catheter movement or catheter blockages).

Unexplained pain at the dermatomal level of the catheter tip.

Unexplained neurological deficit or dysfunction that could be due to compression of the spinal 
cord at the level of a catheter tip.
For the purpose of this study, definite inflammatory granuloma is an intramural extra-medullary mass at 
the catheter tip that is confirmed by an MRI with or without contrast, CT myelogram, or by surgery. If 
only clinical signs are detected, but the inflammatory granuloma or mass cannot be verified by imaging 
or surgery, and no other cause can be determined, the event will be classified as a possible inflammatory 
granuloma. If in the opinion of the investigator there is a reasonable probability that the subject may be
experiencing an inflammatory granuloma, an MRI without and with infusion of a contrast agent, or CT 
myelogram, will be requested. All MRIs and CT myelograms will be assessed by a single central 
independent radiologist who will be blinded to the subject’s history. During the trial, all SAEs reported 
to the investigator shall be reported to the Sponsor or their delegate within 24-hours of the event being 
reported to the investigator. The investigator will be asked to provide details of the SAE, an assessment 
of severity of the event and an opinion as to the cause.
Safety data from the study will be summarized descriptively by dose and product used. Descriptive 
statistics will be calculated for quantitative data and frequency counts and percentages will be provided 
for categorical data. The nature, frequency, and severity of drug related serious adverse events will be 
tabulated for all subjects combined and by treatment. Baseline, within study, end of study, and change-
from-baseline values for vital signs will be summarized as appropriate.
Primary 
Efficacy 
Endpoint
The primary efficacy endpoint is the proportion of subjects who are treatment failures during the 
double-blind randomized withdrawal period (see treatment failure criteria in Study Design section).


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PROTOCOL SYNOPSIS (PAGE 7 of 7)
Secondary 
Efficacy 
Endpoints

Safety of intrathecal hydromorphone hydrochloride as assessed through collection of AEs and 
SAEs during the conduct of the trial. Particular attention will be paid to:
a.
Rate of confirmed granulomas that are verified by MRI with and without contrast, CT 
myelogram or by surgery.
b.
Rate of possible granulomas.

Short-Form McGill Pain Questionnaire (SF-MPQ) (1).

Time to Rescue after Randomized-Withdrawal (2, 3).

Oral Opioid Supplement Consumption.

Brief Pain Inventory (BPI) (4, 5).

Patient Global Impression of Change (PGIC) (6).
Statistics –
Primary 
Endpoint
The primary efficacy endpoint is the proportion of subjects who are treatment failures. The primary 
efficacy analysis will be completed in the Intent-to-Treat population (all randomized subjects) and will 
be carried out using Pearson’s chi-square test at the 0.05 level of significance (two-sided).
The true treatment failure rate in the hydromorphone hydrochloride arm is assumed to be at most 20%.
Based on a two-sided, two-sample comparison of proportions at the alpha=0.05 level of significance, a 
sample size of 80 subjects (40 per arm) will provide greater than 90% power to detect an increase in the 
treatment failure rate of 35 percentage points (ie, the control group has a failure rate of 55%).


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1.0
INTRODUCTION
1.1
Background
Hydromorphone is a potent mu-agonist opioid analgesic that was first marketed in the United 
States in the 1920s. It is primarily used to relieve moderate to severe pain and has been a primary 
treatment for this indication by both oral and injection routes of administration (7, 8). Dilaudid 
was first marketed as an intravenous form of hydromorphone in January 1984 and is now widely 
generic, with more than 25 years of experience in the market in the United States. The oral 
Dilaudid 8 mg formulation (NDA 19-892) was approved in 1992, followed by the 2 mg and 4 mg 
strengths in 2007. Other oral products, such as Palladone and Exalgo, have been approved by the 
Agency; however, intravenous use of hydromorphone is the most common and well-studied 
dosage form.
Hydromorphone Hydrochloride
While used off label for intractable pain by continuous intrathecal administration using 
implanted drug infusion pumps, this route of administration has never been approved by the 
United States Food and Drug Administration (FDA). There are also no well-controlled clinical 
trials that have demonstrated the safety and effectiveness of intrathecal hydromorphone in a 
manner that is compliant with FDA regulations and guidelines. The Sponsor is pursuing the 
formal development of a preservative free intrathecal hydromorphone hydrochloride formulation.
This development program will provide evidence of safety and efficacy for approval by the FDA 
and will be manufactured under GMP conditions with a formulation proven to be compatible 
with intrathecal pumps.
The only FDA approved opioid analgesic for continuous intrathecal use is Infumorph 
(morphine). The FDA has also approved one non-opioid analgesic for intrathecal use, Prialt 
(ziconotide), which is not widely used given the significant side effects and high cost. 
As a result, off-label use of unapproved products is common for intrathecal administration. Some 
estimates are that hydromorphone is used by the intrathecal route of administration in up to 
25,000 persons in the United States and is primarily obtained through poorly controlled 


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pharmacy compounding or by manipulation of Dilaudid-HP (hydromorphone for injection, 
approved for IV infusion), which adds significant risk to the treatment of subjects. Combinations 
with other unapproved drugs, such as clonidine, gabapentin or bupivacaine, are also common.
The purpose of this protocol (CNS-HYD201US) is to support the efficacy of intrathecal 
hydromorphone hydrochloride (referred to in this protocol as hydromorphone) monotherapy 
given by continuous intrathecal administration using a SynchroMed II Implantable pump. The 
results of this protocol will be used to support submission and approval of intrathecal 
hydromorphone from the US FDA for use in subjects with chronic intractable pain.
1.2
Nonclinical Assessments
1.2.1
Pharmacology
Hydromorphone is a phenanthrene-derivative structural analog of morphine; it is essentially 
"dehydroxylated morphine." It may be produced in the body by N-demethylation of 
hydrocodone. The oral bioavailability is roughly 30% to 40%. After intramuscular administration 
of hydromorphone, the analgesic onset is about 10-20 minutes, the time to peak analgesic effect 
is roughly 30 to 60 minutes, the analgesic duration is about 3-5 hours, and the elimination 
half-life is roughly 2 to 3 hours. Hydromorphone has a strong affinity for the mu opioid receptor 
and is as relatively hydrophilic as morphine sulfate. The oral-to-parental ratio is about 5:1 and 
when administered parenterally, roughly 1.5 mg of hydromorphone is equivalent to 10 mg of 
morphine. The major metabolic pathways of hydromorphone are similar to morphine and 
predominantly in the liver via glucuronidation (e.g. hydromorphone-3-glucuronide (H3G], 
hydromorphone-6 glucuronides [H6G]). H3G is similar to M3G, being devoid of analgesic 
activity and potentially leading to a range of dose-dependent neuroexcitatory side effects 
(e.g., allodynia, myoclonus, seizures) (8).
Analgesic effect and mechanism of action
Tejwani and Rattan determined that hydromorphone acts as an agonist at the mu-opioid receptor 
in a study comparing the efficacy of intrathecal hydromorphone and buprenorphine to suppress 
thermal nociception in male Sprague-Dawley rats. An additional objective was to understand 
whether hydromorphone binds and act as agonists to mu-, delta-, and kappa-spinal opioid 
receptors (9). Plummer et al demonstrated that the analgesic effect of intrathecal opioids, 
including hydromorphone, is linear based on a log(dose)-response in relationship to their 
clearance from the cerebrospinal fluid (10).
Allen et. al. measured the full analgesic dose and the maximum tolerated dose for a variety 
opioids in dogs with chronic intrathecal delivery. Drugs examined were morphine sulfate, 
hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-
Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. Six-hour intrathecal infusion of 
agonists resulted in a time-dependent increase in thermal escape latency. At higher 


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concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity 
occurred (11). 
Histamine release
Guedes et. al. found that intravenous hydromorphone induced minimal histamine release. They 
compared plasma histamine concentrations, behavioral and cardiovascular parameters following 
intravenous administration of hydromorphone and morphine in conscious dogs. Plasma 
histamine concentration, noninvasive oscillometric blood pressure, heart rate and rhythm were 
evaluated. Median plasma histamine increased significantly only after the higher dose of 
morphine. Maximum plasma histamine measured was 0.8 ng/mL after saline and, after the lower 
and higher doses, respectively, 10.2 and 9.7 ng/mL for hydromorphone, and 440 and 589 ng/mL 
for morphine. One dog became hypotensive immediately after receiving the highest dose of 
morphine. Occasional ventricular premature contractions occurred in one dog with both opioids 
and dosages. No dogs vomited or defecated, but all salivated profusely with both opioids. 
Neuroexcitation occurred in four dogs following each opioid (12).
In conclusion, the analgesic properties and mechanism of action of intrathecal hydromorphone as 
a potent agonist of the mu-opioid receptor is well understood and documented in the literature 
(7). The analgesic potency of hydromorphone via the intrathecal route versus systemic is 
believed to be approximately six to ten fold higher than morphine and this potency may be in 
part related to the clearance from the cerebrospinal fluid (13, 14). The ratio of analgesic dose to 
the maximum tolerated dose was studied in the dog and was found to be 1 to 3 for intrathecal 
hydromorphone, thus there is an adequate margin of safety by this route of administration (14). 
Hydromorphone was found to differ from morphine in being a negligible inducer of histamine 
release in the dog and may be associated with fewer side effects related to histamine release (15).
1.2.2
Toxicology
1.2.2.1 Mutagenic and Carcinogenic Toxicity
No carcinogenicity studies have been conducted in animals with hydromorphone according to 
the US product insert (physician labeling) for Dilaudid-HP. Hydromorphone was not mutagenic 
in the in vitro Ames reverse mutation assay, or in the human lymphocytes chromosome 
aberration assay. Hydromorphone was not clastogenic in the in vivo mouse micronucleus assay.
1.2.2.2 Genetic and Teratogenicity Studies
No effects on fertility, reproductive performance, or reproductive organ morphology were 
observed in male or female rats given oral doses of hydromorphone by intravenous 
administration up to 7 mg/kg/day.


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1.3
Clinical Experience
1.3.1
Overview of Clinical Pharmacology
Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic activity of 
analgesia. A significant feature of the analgesia is that it can occur without loss of consciousness. 
Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood 
changes, mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic 
changes. Many of the effects described below are common to the class of mu-opioid analgesics, 
which includes morphine, oxycodone, hydrocodone, codeine, and fentanyl.
Opioids can interact with drugs that increase the effects of serotonin. These include 
antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin and 
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 
receptor antagonists, drugs that effect the serotonin neurotransmitter system (eg., mirtazapine, 
trazodone, tramadol), monoamine oxidase (MAO) inhibitors, (those intended to treat psychiatric 
disorders and also others, such as linezolid and intravenous methylene blue). The interaction 
could cause a rare but potentially life-threatening condition called serotonin syndrome. Subjects 
taking an opioid along with a serotonergic medicine should seek medical attention immediately 
if symptoms such as agitation; hallucinations; rapid heart rate; fever; excessive sweating; 
shivering or shaking; muscle twitching or stiffness; trouble with coordination; and/or nausea, 
vomiting, or diarrhea are experienced. The symptoms generally start within several hours to a 
few days of taking an opioid with another medication that increases the effects of serotonin in 
the brain, but symptoms may occur later, particularly after a dose increase57.
Taking opioids may lead to a rare, but serious condition called adrenal insufficiency in which the 
adrenal glands do not produce adequate amounts of the steroid hormone, cortisol, particularly 
during stressful conditions. Seek medical attention if you experience symptoms of adrenal 
insufficiency such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low 
blood pressure57.
Long-term use of opioids may be associated with decreased sex hormone levels. Inform your 
study doctor if you experience signs or symptoms of low libido, impotence, erectile dysfunction, 
lack of menstruation, or infertility57.
Central Nervous System (CNS)
The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS 
opiate receptors have been identified, and opioids are believed to express their pharmacological 
effects by combining with these receptors. Hydromorphone depresses the cough reflex by direct 
effect on the cough center in the medulla. Hydromorphone produces respiratory depression by 
direct effect on brain stem respiratory centers. The mechanism of respiratory depression also 
involves a reduction in the responsiveness of the brain stem respiratory centers to increases in 
carbon dioxide tension. Hydromorphone causes miosis. Pinpoint pupils are a common sign of 


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opioid overdose, but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic 
origin may produce similar findings). Marked mydriasis rather than miosis may be seen with 
hypoxia in the setting of Dilaudid Injection or Dilaudid-HP overdose.
Gastrointestinal Tract and Other Smooth Muscle
Gastric, biliary and pancreatic secretions are decreased by opioids such as hydromorphone. 
Hydromorphone causes a reduction in motility associated with an increase in tone in the gastric 
antrum and duodenum. Digestion of food in the small intestine is delayed and propulsive 
contractions are decreased. Propulsive peristaltic waves in the colon are decreased, and tone may 
be increased to the point of spasm. The end result is constipation. Hydromorphone can cause a 
marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.
Cardiovascular System
Hydromorphone may produce hypotension as a result of either peripheral vasodilation, release of 
histamine, or both. Other manifestations of histamine release and/or peripheral vasodilation may 
include pruritus, flushing, and red eyes. Effects on the myocardium after intravenous 
administration of opioids are not significant in normal persons, vary with different opioid 
analgesic agents and vary with the hemodynamic state of the subject, state of hydration and 
sympathetic drive.
1.3.2
Overview of Clinical Pharmacology
Distribution
At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. 
After an intravenous bolus dose, the steady state of volume of distribution [mean (%cv)] is 302.9 
(32%) liters.
Metabolism
Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 
95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-
hydroxy reduction metabolites.
Elimination
Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the 
dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy 
reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The 
terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours.


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Hepatic Impairment
After oral administration of hydromorphone at a single 4 mg dose orally, the mean exposure to 
hydromorphone (Cmax and AUC0-∞) is increased 4 fold in subjects with moderate (Child-Pugh 
Group B) hepatic impairment compared with subjects with normal hepatic function. Due to 
increased exposure of hydromorphone, subjects with moderate hepatic impairment should be 
started at a lower dose and closely monitored during dose titration. The pharmacokinetics of 
hydromorphone in subjects with severe hepatic impairment has not been studied. A further 
increase in Cmax and AUC of hydromorphone in this group is expected. As such, the starting dose 
should be even more conservative and the dose titration should be more cautious than with 
persons with non-impaired liver function.
Renal Impairment
After oral administration of hydromorphone at a single 4 mg oral dose, mean exposure to 
hydromorphone (Cmax and AUC0-48) is increased in subjects with impaired renal function by 
2-fold, in moderate (CLcr = 40 - 60 mL/min) renal impairment and 3-fold in severe 
(CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In 
addition, in subjects with severe renal impairment hydromorphone appeared to be more slowly 
eliminated with a longer terminal elimination half-life (40 hr) compared to subjects with normal 
renal function (15 hr). Subjects with moderate renal impairment should be started on a lower 
dose. Starting doses for subjects with severe renal impairment should be even lower. Subjects 
with renal impairment should be closely monitored during dose titration.
Pediatrics
Pharmacokinetics of hydromorphone has not been evaluated in children.
Geriatric
The effect of age on the pharmacokinetics of hydromorphone has not been adequately evaluated.
Gender
Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have a 
higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax
may not be clinically relevant.
Pregnancy and Nursing Mothers
Hydromorphone crosses the placenta. Hydromorphone is also found in low levels in breast milk, 
and may cause respiratory compromise in newborns when administered during labor or delivery.


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1.3.3
Overview of Efficacy and Safety
Efficacy of Intrathecal Hydromorphone:
There is extensive literature on the use of intrathecal hydromorphone use in subjects with 
intractable pain. These reports have also led to the common use of hydromorphone in practice, 
with either compounded hydromorphone being used for intrathecal delivery or Dilaudid® for 
injection being filled into intrathecal pumps often with manipulation of the formulation. The off-
label use of intrathecal hydromorphone is discussed in an article by Lee et. al. (16) that evaluated
literature in support of hydromorphone, but concludes that the risk of unlicensed use of 
hydromorphone as an intrathecal product may pose more risks than the potential benefit.
Several review articles and management guidelines have also been published that compare the 
use of intrathecal morphine and hydromorphone, including the dose, efficacy and safety.
Guidelines for intrathecal drug delivery for the management of pain have been published by 
several major pain management organizations (16-19).
A review article entitled “Hydromorphone for Acute and Chronic Pain” (19) reports data from 48 
studies (3510 participants). Of these studies 5 of the 48 studies were placebo-controlled, 43 of 48 
studies compared hydromorphone use with other opioids, bupivacaine and with itself with 
different formulations and routes of administration including intrathecal. The author concludes
that hydromorphone appears to be a more potent analgesic, but that there is little difference 
between morphine and hydromorphone in terms of efficacy, adverse effect profile and subject
preference. 
Other review articles also provide important data on the of intrathecal opioids, including 
hydromorphone (14,15, 20-31). The use in children is also examined and provides some 
evidence of the effectiveness of intrathecal hydromorphone in the pediatric population (32).
These articles also establish a conservatively safe starting dose for intrathecal hydromorphone is 
0.5 mg/day with titration up to 10 mg/day. The rate of titration was also evaluated and even a 
rapid titration of 2 mg/day appeared to be safe and acceptable. These articles considered 
hydromorphone as a first line treatment by the intrathecal route of administration. The 
publication also suggests a maximum concentration for the formulation used in the intrathecal 
pump of 30 mg/mL to avoid increased risk of granulomas. These articles also look at 
retrospective evaluations of intrathecal hydromorphone use and the efficacy in severe pain 
populations. The general conclusions presented were that intrathecal hydromorphone is safe and 
at least as effective as morphine, with the potential for some benefits.
Although there are no randomized controlled studies of hydromorphone administered 
intrathecally, there are retrospective and prospective studies that have specifically examined the 
efficacy and safety of intrathecal hydromorphone alone or in combination (32-38). 
Anderson et al (39) retrospectively reviewed 37 subjects with chronic nonmalignant pain 
managed with intrathecal hydromorphone after failure of intraspinal morphine. All subjects 


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suffered from severe nonmalignant pain, most from failed lumbosacral spine operations (19/37; 
51%). Morphine was replaced with hydromorphone because of pharmacological complications 
(21/37; 57%) or inadequate analgesic response (16/37; 43%) after an average of 11 months of 
intrathecal therapy. Adverse events, particularly nausea and vomiting, pruritus, and sedation were 
reduced by hydromorphone in most subjects. Peripheral edema was improved by hydromorphone 
but tended to recur with prolonged hydromorphone exposure. Analgesic response was improved 
by at least 25% in six of 16 subjects who were switched to hydromorphone because of poor pain 
relief. Du Pen et al (17) retrospectively reviewed 24 subjects with noncancer-related chronic pain 
receiving hydromorphone monotherapy. Average pain scores decreased significantly (p = 0.03).
Dominguez et al (40) found that half of 86 subjects in a retrospective review required either a 
switch to hydromorphone from morphine or adjuvants were added to morphine by 18 months 
after initiation of intrathecal morphine therapy. Ackerman et. al. (36) retrospectively examined 
intrathecal clonidine and combination opioid/clonidine. Of 7 clonidine monotherapy treatment 
failure, 3 added hydromorphone, 1 of whom failed the combination therapy. Deer et al (38)
retrospectively examined intrathecal ziconotide and opioid ziconotide therapy. Seven of 16 
subjects studied received hydromorphone. These retrospective studies confirm the common use 
of hydromorphone alone or in combination in present-day clinical practice in intrathecal therapy 
despite lack of high-quality randomized clinical studies to characterize its effectiveness and 
safety.
Safety of Intrathecal Hydromorphone:
A major difference in the pharmacology of hydromorphone versus morphine is that morphine 
induces histamine release while hydromorphone does not (40, 41). This difference may be 
responsible for reports of decreased pruritus in subjects switched from morphine to 
hydromorphone (42). Potential improvements in other histamine-related morphine adverse 
events such as peripheral vasodilation and hypotension by switching to hydromorphone have not 
been investigated although a study in morphine versus fentanyl did find histamine release by 
morphine to be related to differences in these adverse events between these two drugs (12).
A metabolite of hydromorphone, hydromorphone-3-gucuronide, has been demonstrated to 
accumulate in chronic renal failure, perhaps producing neuropsychological effects including 
cognitive impairment (8, 43).
Case reports related to safety include a subject extracting hydromorphone from his pump (44), 
injection of hydromorphone into the subcutaneous pocket around the intrathecal pump (45), and 
a pontine hemorrhage following implantation of the pump and initiation with 
hydromorphone/bupivacaine (46); the subject had a previously undiagnosed underlying 
metastatic lesions.
A major complication of intrathecal drug therapies is the formation of inflammatory masses at 
the catheter tip (granulomas) (47, 48) that, if undetected, can lead to irreversible neurological 
effects. Several review articles in the literature also evaluate the risk of mass formations or 


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granulomas at the catheter tip with both morphine and hydromorphone (49-51). These 
publications describe case studies of events where a mass formation or granuloma formed during 
the use of an intrathecal implantable pump.
In a surveillance study Deer (52) found that the majority of cases reported in the literature were 
due to morphine. Among 208 subjects receiving intrathecal therapy, 3% (6/208) were found to 
have a significant lesion by imaging. Five were asymptomatic. No specific characteristics, such 
as drugs or concentrations were identified. All 6 subjects had percutaneous catheter revisions 
without complication. The Coffey et. al. (50) publication reviewed more than 40 cases of
suspected granulomas, of which most were caused by mixtures of opioids and other agents, but 
some were from the use of only morphine or hydromorphone. Thus the risk of a granuloma 
exists, but given the low number of reports compared to the high utilization of intrathecal pumps 
to administer morphine or hydromorphone, the actual frequency of such events is considered 
extremely low.
Symptoms from granulomas are motor weakness, sensory loss, changes in reflex functions, and 
bladder dysfunction. Other symptoms can be numbness, tingling, burning, hyperesthesia, 
hyperalgesia, and radicular pain at the same level as the catheter tip. A granuloma is suspected 
when the required amount of opioids increases for the same amount of analgesia effect and pain 
control (52). Precipitated drug, however, can mimic a granuloma, which are usually distinct, 
globular spheroid-shaped lesions best visualized on T1 MR image sequences with gadolinium 
contrast (49). Preliminary evidence suggests that dural mast cell degranulation and concomitant 
release of inflammatory mediators such as histamine may be responsible for the formation of 
these (51). In animal studies, however, opiates at equianalgesic doses differ in the rate of 
granuloma formation (53, 54).
Granulomas have been reported most commonly with morphine. Other drugs have also been 
implicated in causing this complication, including hydromorphone, fentanyl, and tramadol (11, 
54, 55). Animal studies in the sheep may indicate that at equivalent daily doses (e.g. 12 mg/day) 
hydromorphone has less potential to induce an inflammatory mass or granuloma than morphine
(21, 33). Given that hydromorphone is at least five-times more potent than morphine, these 
observations may explain the belief of physicians that hydromorphone has fewer side effects and 
potential for granuloma in that the dose and concentration at the catheter tip during infusion is far 
less with hydromorphone than morphine. The daily dose and concentration are considered the 
primary factors that induce a granuloma the lower dose and slower infusion rate resulting in a 
lower concentration in the area of the catheter tip, would be predicted based on these animal 
models to have a lower potential of granuloma formation than with intrathecal morphine.
In addition to the literature, Medtronic Inc. has conducted a large publicly available post-
approval surveillance study for the SynchroMed® II Programmable Pump that also includes 
surveillance of various drug products delivered by IT administration. This study followed 
4,384 subjects with implanted SynchroMed® II Programmable Pump drug delivery systems at 
fifty centers, with 3,101 subjects receiving various other IT medications for pain. This study also 


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included subjects receiving intrathecal morphine (Infumorph). Medtronic’s study was a careful 
examination of inflammatory granuloma formation in subjects. An inflammatory granuloma in 
the Medtronic surveillance study was defined as “an intradural extra medullary mass at the 
catheter tip that could be visualized by enhanced MRI imaging.” The criteria for diagnosing such 
a granulomatous mass is based on several clinical signs and symptoms: a decrease of drug effect 
and new radicular pain and/or cord compression, MRI findings of an enhancing mass at the 
catheter tip on the T-1 infusion and surgical or histological confirmation.
From 2003 to 2010 six cases of confirmed or probable inflammatory granuloma were noted as 
well as six cases of possible granuloma out of the 4,384 subjects evaluated (12/4384, 0.27%). All 
of these subjects were being treated with intrathecal morphine for severe, intractable pain.
Literature reviews of intrathecal hydromorphone use have not reported significant risk of 
granuloma formation. While there is no well-controlled trial with hydromorphone that examines 
the risk of granuloma formation, the potential is not considered to be higher than with 
Infumorph. Other side effects may be improved with hydromorphone, including the complication 
of drug dependency.
Based on the literature and wide spread use of off-label hydromorphone, there is potential that 
intrathecal hydromorphone has a similar, if not superior, efficacy and safety profile to that of 
intrathecal morphine. The risks do not appear from all literature to be greater than morphine use.
The most skeptical publications imply that there may be no significant difference in either safety 
or efficacy between intrathecal morphine and hydromorphone, but that having two alternatives is 
beneficial in allowing drug rotations that may help reduce tolerance and the need for increased 
doses and worsening of side effects. Thus, the rationale for a formal development program for 
intrathecal hydromorphone to establish the efficacy and safety, as well as a GMP formulation 
demonstrated to be compatible in the intrathecal implantable pumps would appear to have a 
positive benefit risk profile based on all available information.
1.4
Study Rationale
This is a controlled, prospective, randomized withdrawal trial to be conducted at 10 to 30 US 
clinical trial sites that are experienced with the use of intrathecal opioids. The primary objective 
of this study is to demonstrate the efficacy and safety of intrathecal hydromorphone
hydrochloride.
Subjects who currently have a SynchroMed® II Implantable Infusion Pump will be eligible to 
enroll in this trial. The reason for restricting the efficacy study to one intrathecal infusion pump 
is to avoid confounding factors and adverse effects that may be pump related.
For subjects that do not have a current infusion pump implanted, they may be consented and 
enrolled after pump implantation and stabilization on intrathecal morphine. Given that the study 
will allow direct switching from other opioids to hydromorphone hydrochloride, and the fact that 
morphine is approved for administration by intrathecal infusion, titration of subjects according to 
the approved morphine labeling is recommended in this trial (CNS-HYD201US).


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Subjects entering the study should have a reasonable likelihood of benefiting from intrathecal 
treatment with an opioid such as hydromorphone hydrochloride. Thus, for subjects who are 
already on intrathecal opioid therapy at a dose that is at or approaching an equivalent dose to 
10 mg hydromorphone hydrochloride by intrathecal administration it may be questionable if they 
will benefit from this therapy. As such, the investigator should use their judgment in enrolling 
subjects to ensure that there is a good probability that the person will experience reasonable pain 
control and be eligible for the double-blind period (ie, can achieve a 5 day average pain intensity 
score of 50 mm or less on a 100 mm scale).
All subjects will be converted from their current intrathecal therapy to intrathecal 
hydromorphone hydrochloride according to standard medical practice in a 1:6 or 1:12 ratio based 
on their previous morphine dose and tolerance of intrathecal opioid therapy. If already on a 
stable dose of compounded hydromorphone hydrochloride, subjects may be converted directly to 
study medication at a 1:1 ratio. This conversion scheme is consistent with current medical 
practice of intrathecal pain physicians. Medical practice in switching subjects is to convert the 
subject based on a 1:6 ratio of hydromorphone to morphine if the subject is tolerating therapy 
well. Depending on the subject’s dose and general condition, a safety factor of up to 50% is 
sometimes used but in general is not considered necessary by most practicing intrathecal pain 
physicians. As such, a conversion scheme of 1:6 or 1:12 is planned based on starting morphine 
dose and subjects tolerance to that dose. After the initial replacement of medication with 
hydromorphone hydrochloride, the subject should be contacted by telephone 24 hours after 
initiating study medication. Dose adjustments are then planned according to the protocol to 
achieve an optimal dose of hydromorphone hydrochloride.
For the CNS-HYD201US trial, only hydromorphone hydrochloride may be used in the infusion 
pump to help assess the safety and effectiveness as a monotherapy. Given many subjects are on 
combination intrathecal treatment, if another concomitant medication by IT is necessary, it 
should be given orally, if possible. If other required medications in the pump cannot be given 
effectively by oral administration, then the subject will not be eligible for the CNS-HYD201US 
trial.
Dosing with the SynchroMed II Implantable Infusion pump may be by simple continuous, 
complex continuous with or without use of a Personal Therapy Manager (PTM) dosing. For 
those subjects who are dosed using simple continuous or complex continuous dosing, the total 
daily dose will be considered and documented. Subjects on PTM dosing will be allowed as long 
as the maximum allowed dose is less than or equal to 10 mg/day. PTM dosing will be recorded 
as the base continuous dose and the maximum dose allowed by the PTM.
The purpose of the 12-week open label period of the trial is to titrate subjects to an optimal dose 
of hydromorphone hydrochloride and demonstrate the ability to maintain adequate pain relief in 
subjects requiring intrathecal opioid therapy. During the open label period of this trial up to Day 
77, subjects may be given oral supplemental medication up to a maximum of 180 mg-equivalent 
morphine per day to manage pain during the titration to an optimal dose. The subject should be 


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weaned off this oral supplement as much as possible as the intrathecal dose of hydromorphone 
hydrochloride is optimized. Prior to randomization from Day 77 to 83, the goal is to demonstrate 
adequate pain relief without oral supplement, defined as an average VASPI score of 50 mm or 
less based on the last 5 days with nonmissing pain scores. During the double-blind period from 
Day 84 to 119, up to 60 mg per day of oral morphine-equivalence of opioid is permitted and is
intended only for the purpose of managing withdrawal symptoms in subjects who may require 
some intervention. The 60 mg per day morphine-equivalence dose of opioid is expected to help 
relieve possible withdrawal effects, but is not intended to significantly impact pain. Doses of oral 
opioids, any change in prescription medications, or any changes to non-pharmacologic
interventions intended to manage pain, will constitute treatment failure.
Given subjects on strong intrathecal opioids cannot be abruptly withdrawn, during the 
randomization phase one group will remain on their optimal dose of therapy, while the other 
control group is weaned off therapy over a 4 week period followed by 1 week at the lowest pump 
setting. It is anticipated that most subjects in the group whose dose of intrathecal opioids is being 
titrated downward will fail treatment prior to reaching a near 0% dose. The final step of the 
titration will be to place the pump in shipping mode, which lowers the speed to 0.005 mL/day.
Subjects may rescue based on intolerable pain at any time and will be considered a treatment 
failure, or if their 5 day average pain intensity score is 20 mm greater than their baseline score 
prior to randomization they will also be considered a treatment failure.
Subjects, whether they enter the 5-week randomized withdrawal period or not, who meet the 
inclusion criteria for the CNS-HYD202US safety trial, and would like to participate in the 
12-month extension, will be allowed to continue on intrathecal hydromorphone hydrochloride as 
part of that study. All subjects who were in the group whose dose of intrathecal opioids is being 
titrated downward may be titrated back to an effective dose of intrathecal hydromorphone
hydrochloride as part of the CNS-HYD202US trial. All subjects will be entered after signing an 
IRB approved informed consent. Subjects will be followed for safety for the duration of their 
treatment with intrathecal hydromorphone hydrochloride using the SynchroMed® II 
Programmable Pump or until the study is terminated after the 12-month safety follow up study.
2.0
PURPOSE AND STUDY OBJECTIVES
2.1
Purpose
The purpose of this clinical study is to demonstrate the efficacy and safety of a 2 mg/mL and 
10 mg/mL formulation of hydromorphone hydrochloride dosed by the intrathecal route of 
administration in subjects with chronic pain that require continuous opioid treatment through an 
implantable micro-infusion pump.


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2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this clinical trial is to demonstrate the superiority of intrathecal 
hydromorphone hydrochloride in subjects who are on an optimal dose compared with those who 
have their dose titrated downward during the randomized withdrawal period as measured by 
treatment failure rate.
2.2.2
Secondary Objective
To evaluate the safety of hydromorphone hydrochloride given by the intrathecal route of 
administration.
3.0
STUDY DESIGN
3.1
Description of Trial Design
This is a controlled, prospective, randomized withdrawal trial to be conducted at 10 to 30 clinical 
trial sites that are experienced with the use of intrathecal opioids. All subjects will be entered 
after signing an IRB approved informed consent. Subjects who currently have a SynchroMed® II 
Implantable Infusion Pump will be eligible to enroll in this trial. Subjects who are naïve to 
intrathecal therapy, may be enrolled 2-weeks after pump implantation. Subjects entering the 
study should have a reasonable likelihood of benefiting from intrathecal treatment with an opioid 
such as hydromorphone hydrochloride.
Subjects entering the trial on a therapeutic dose of intrathecal hydromorphone hydrochloride may 
be converted directly to study medication without dose adjustment.
Subjects who will be converted from their current intrathecal morphine therapy to intrathecal 
hydromorphone hydrochloride according to the following scheme:
Subject Status on Morphine
Conversion 
Ratio
Dose ≤ 30 mg IT morphine and tolerating therapy well
1 : 6a
Dose > 30 mg IT morphine or subject has significant side effects 
on morphine
1 : 12b
aConversion is based on mg-morphine equivalence such that for each 6 mg morphine sulfate, the dose is 
converted to 1 mg hydromorphone hydrochloride.
bConversion is based on mg-morphine equivalence such that for each 12 mg morphine sulfate, the dose is 
converted to 1 mg hydromorphone hydrochloride.


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The conversion will take place by removing the current product in the pump and then replacing 
the contents with hydromorphone hydrochloride for intrathecal injection. At the discretion of the 
investigator the pump reservoir may be rinsed with preservative free sterile saline or the study 
medication (hydromorphone hydrochloride for injection). The subject should be contacted by 
telephone 24 hours after initiating study medication. If combinations are used in the previous 
intrathecal therapy, oral medications may be provided to replace the intrathecal combination 
regimen. However, for the duration of the CNS-HYD201US trial only hydromorphone 
hydrochloride may be used in the intrathecal pump as monotherapy. Depending on the subjects 
starting dose on hydromorphone hydrochloride, either a 2 mg/mL or 10 mg/mL formulation of 
hydromorphone hydrochloride for intrathecal injection may be used. Dosing with the 
SynchroMed II Implantable Infusion pump may be by simple continuous, complex continuous or 
PTM dosing.
Dose adjustments thereafter will be allowed by adjusting the pump speed based on the following 
scheme:
Dose of Hydromorphone 
Hydrochloride IT
Maximum Dose 
Adjustment
0.1 to 0.5 mg/day
50 %
> 0.5 mg/day
25 %
A maximum dose of 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any 
time during this study. For PTM dosing this maximum dose includes the patient activated doses 
that are allowed by the device programming. Subjects may be given oral supplemental 
medication up to Day 77 up to a maximum of 180 mg-equivalent morphine per day, however, the 
objective of the trial during this period is to achieve an optimal dose of intrathecal 
hydromorphone hydrochloride and reduce or eliminate any oral supplement. Oral supplement in 
excess of 180 mg-equivalent morphine per day or other interventions due to intolerable pain, is 
not permitted.
On Day 77 the pump should be refilled with intrathecal hydromorphone and any final 
adjustments made to the daily dose or programming. On Day 77, the subject will be given a 
remote monitoring device to measure VASPI scores twice daily in the morning (5:30 am to 
12:00 noon) and in the evening (6:00 pm to 11:45 pm). After Day 77 and during the randomized 
double-blind period there should be no dose adjustments other than those dictated by the protocol 
for subject in the control arm whose dose of intrathecal opioids is being titrated downward.
After Day 77, there should also be no changes to the pump programming for simple continuous, 
complex continuous or PTM dosing regimens until after the completion of the trial.
At the end of the 12 week chronic dosing period, subjects who meet criteria for randomization 
will be assigned to either remain at their current dose of hydromorphone hydrochloride or to 
have their dose titrated downward (control group) in a blinded fashion. The criteria for 
randomization is defined as a an average VASPI score of 50 mm or less on a scale of 100 mm for 


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the last 5 days with daily pain measurements prior to randomization on Day 84. After Day 77 the 
subject should be off all oral opioid supplements and should have no change in other prescription
pain medications or non-pharmacologic interventions they are receiving for pain management.
For those subjects randomized to be withdrawn from therapy with hydromorphone hydrochloride
on Day 84, the pump speed will be adjusted to decrease the dose each 7 days (± 1 day), starting 
at a dose of 75%, 50%, 25%, 12.5% and approximately 0% of the dose at the time of 
randomization. For PTM dosing, the base continuous dose and the PTM dose would be 
decreased by the specified percentages above. The total maximum dose of 10 mg/day will be the 
combined total of the decreased base dose and PTM dose. 
For those subjects randomized to stay on their current dose of hydromorphone hydrochloride, 
they will also return to the clinic on the same schedule for assessments and for mock pump 
adjustments. The blind will be maintained by having an independent unblinded medical 
professional at the site manage the pump infusion rate and medication provided to the subject. 
Pain assessments using the VASPI scale will continue twice daily, once in the a.m. (between 
5:30 am and 12:00 noon) and once in the p.m. (between 6:00 pm and 11:45 pm) for the 7 days 
prior to the randomization period and throughout the randomized withdrawal period. COWS and 
SOWS assessments will be performed at specified time points to assess any withdrawal 
symptoms. Subjects will be permitted a maximum of 60 mg of morphine-equivalence of oral 
opioid per day during the randomized withdrawal period (Day 84 to 119) only for the purpose of 
managing withdrawal symptoms. Use of oral opioids, any change in non-opioid prescription 
medications, or any changes to non-pharmacologic interventions intended to manage pain during 
the double-blind period will constitute treatment failure.
Baseline pain for the double-blind randomized withdraw period is defined as the average of the 
last 5 days with daily pain measurements while on an optimal intrathecal dose of hydromorphone
hydrochloride, between Days 77 and 83 of the open-label dosing period. 
Treatment Failure Criteria: After randomization, a treatment failure will be defined by the 
following criteria:
1. A subject who experience an increase of 20 mm or more above the baseline value on a 
100 mm VASPI based on the average of 5 days, or
2. A subjects who experience intolerable pain that in the opinion of the investigator requires 
intervention (i.e. rescue), or
3. Any subject who has other interventions for pain that violate the protocol from Day 84 to 
119 that includes:
a.Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent to 
manage withdrawal symptoms, or
b.Has a change in non-opioid oral prescription medications or non-pharmacological 
treatments being administered for the management of pain.


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Note: A subject who does not have sufficient data for evaluation, drops out for any other 
reasons that are not listed above or who experiences withdrawal syndrome as identified by 
COWS > 12 during the double-blind treatment phase will not be classified as a treatment 
failure in the primary efficacy analysis.
Prior to rescue medication being administered, subjects will complete Day 119 study 
assessments, if possible. After confirming with the investigator that it is acceptable to take rescue 
medication, if a subject cannot return to the study site for assessments they will be instructed to 
complete a VASPI score on the remote monitoring device immediately prior to taking oral rescue 
medication. If the subject can return to the site, rescue may be performed by either oral or IV 
medication being administered or by increasing the pump speed to achieve a therapeutic dose of 
hydromorphone hydrochloride, or both.
Subjects who are treatment failures or those who are dropped from the study prior to 
randomization under this protocol will be permitted to enroll into Mallinckrodt clinical study 
CNS-HYD202US if the PI believes that the subject meets the study selection criteria and would 
benefit from participation in the study. For any subject continuing therapy on the 
CNS-HYD202US trial, the Day 119 (or failure visit) assessments will be considered the last day 
on the CNS-HYD201US trial and the first day of CNS-HYD202US. Subjects in the 
CNS-HYD201US trial who were dropped prior to randomization and judged by the primary 
physician to benefit from participation in CNS-HYD202US will complete the study visit that 
they are on, go directly into CNS-HYD202US and complete scales there at the Screening and 
Baseline Visit. Subsequent visits, including re-titration onto hydromorphone hydrochloride if 
necessary, will be considered part of the CNS-HYD202 US trial.
Subjects will be evaluated for side effects and clinical complications associated with the use of 
intrathecal hydromorphone hydrochloride. Signs and symptoms of an inflammatory granuloma, 
including radicular pain, loss of drug efficacy, and spinal cord compression will be monitored by 
clinical assessments. If there are clinical signs or symptoms identified which may indicate an 
inflammatory mass formation, an MRI scan with and without contrast or CT myelogram, will be 
performed to evaluate the potential presence of an inflammatory granuloma as opposed to other 
catheter related problems that may result in reduced delivery or clinical symptoms. Events that 
may be related to an inflammatory granuloma will be classified as with confirmed granuloma, 
suspected granuloma, other catheter related problem (confirmed not caused by a granuloma) or 
other clinical even caused by the underlying disease or other non-catheter/product related event.
Following the 5 week randomized withdrawal period, or if a subject is rescued and completes the 
failure assessment visit, all subjects that entered the randomization period may be allowed to 
continue on intrathecal hydromorphone hydrochloride for up to 12-months of safety evaluation 
by entering the open-label safety study (CNS-HYD202US), with all subjects who were 
withdrawn from optimal therapy being titrated back onto intrathecal hydromorphone 
hydrochloride. A subject who is a treatment failure or who is dropped from the study prior to 
randomization can enroll into the long term safety study (CNS-HYD202US) if the subject meets 


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the inclusion/exclusion criteria for CNS-HYD202US. Subjects who cannot tolerate intrathecal 
hydromorphone hydrochloride during the 12-week chronic dosing period will not be eligible for 
the long term treatment protocol. 
3.2
Study Endpoints
3.2.1
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects who are treatment failures during the 
double-blind randomized withdrawal period.
Treatment Failure Criteria: After randomization, a treatment failure will be defined by the 
following criteria:
1. A subject who experience an increase of 20 mm or more above the baseline value on a 
100 mm VASPI based on the average of 5 days, or
2. A subjects who experience intolerable pain that in the opinion of the investigator requires 
intervention (ie, rescue), or
3. Any subject who has other interventions for pain that violate the protocol from Day 84 to 
119 that includes:
a.Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent to 
manage withdrawal symptoms, or
b.Has a change in non-opioid oral prescription medications or non-pharmacological 
treatments being administered for the management of pain.
Note: A subject who does not have sufficient data for evaluation, drops out for any other 
reasons that are not listed above or who experiences withdrawal syndrome as identified by 
COWS > 12 during the double-blind treatment phase will not be classified as a treatment 
failure in the primary efficacy analysis.
3.2.2
Secondary Endpoints
The most important secondary endpoint is:

Safety of intrathecal hydromorphone hydrochloride as assessed through collection of AEs 
and SAEs during the conduct of the trial. Particular attention will be paid to:
o
Rate of confirmed granulomas that are verified by MRI with and without contrast, CT 
myelogram or by surgery.
o
Rate of possible granulomas.
Other secondary endpoints include:

Short-Form McGill Pain Questionnaire (SF-MPQ) (1).

Time to Rescue after Randomized-Withdrawal (2, 3).

Oral Opioid Supplement Consumption.


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
Brief Pain Inventory (BPI) (4, 5).

Patient Global Impression of Change (PGIC) (6) .
3.3
Diagnosis of Granuloma 
The use of intrathecal morphine has been associated in rare cases with a granuloma at the 
catheter tip that can result in serious neurological impairment, including paralysis. These events 
have been reported infrequently with hydromorphone hydrochloride and are more commonly 
associated with use of combinations of compounded drugs or high concentration formulations.
Nevertheless, the potential for a granuloma or mass will be assessed at each visit to the 
investigator.
Clinical signs and symptoms that may indicate a granuloma include:
o
A sudden decrease in therapeutic response requiring increased daily doses that is not
attributed to other assignable causes (e.g. mechanical failures, catheter movement or 
catheter blockages).
o
Change in the character, quality, or intensity of the subjects pain (ie, is less well 
managed).
o
Unexplained pain at the dermatomal level of the catheter tip.
o
Unexplained neurological deficit or dysfunction that could be caused by mass effect at 
the spinal level of the catheter tip.
For the purpose of this study to establish that there is a definite granuloma, an MRI (with and 
without contrast) or CT myelogram must demonstrate an intradural extra-medullary mass near 
the catheter tip. If only clinical signs are detected, but the granuloma or mass cannot be verified 
by MRI, CT myelogram or surgery, and no other cause can be determined, the event will be 
classified as a possible or suspected granuloma.  
If in the opinion of the investigator there is a reasonable probability that the subject may be 
experiencing a granuloma, an MRI with and without infusion of a contrast agent or a CT 
myelogram will be requested. All MRI or CT myelograms will be assessed by a single central 
independent radiologist who will be blinded to the subject’s history.
3.3.1
Treatment of Granuloma
If a granuloma is detected the subject will be considered a treatment failure and discontinued
from the trial. If the granuloma is confirmed early in its clinical course, depending upon an 
individual subject's clinical condition, intraspinal therapy may be continued after one of the 
following interventions: 
o
Withdraw the catheter to a level below the granuloma. 
o
Remove the involved catheter and replace it with a new catheter positioned below the 
granuloma. 


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o
Lower the IT dose or replace with saline until the inflammatory mass resolves.
o
Disconnect the involved catheter from the connector (two-piece catheter), or transect 
the involved catheter above the level of the lumbodorsal fascia (one-piece catheter) 
leaving the intraspinal catheter segment undisturbed. Ligate the exposed end of 
involved catheter to prevent CSF loss. Implant a new catheter with its tip below the 
granuloma, and connect the new catheter to the proximal (pump) catheter segment. 
Prompt open surgical removal of the granuloma or decompression of the spinal cord should
only be considered in subjects who have a significant or progressive neurological deficit. 
3.4
Measures to Minimize Bias
3.4.1
Blinding
This is a double-blind, randomized study. After randomization on Day 84, subjects will receive 
either intrathecal hydromorphone hydrochloride or will have their dose titrated downward over a 
4 week period followed by 1 week at the minimal pump setting or shipping mode (ie,
0.005 mL/day). An unblinded technician or nurse at the site will be assigned (ie, Pump Operator)
to adjust pump speeds during the 5 week double-blind period. The unblinded pump operator will 
not be involved in any other evaluations of the subject and will be instructed to avoid revealing 
any information to study personnel about the group assignment of the subject. Dosing after 
randomization will be done by randomization code for each subject. Subjects who utilize a PTM 
device will be blinded to the display screen of the PTM. The display screen will be covered with 
a non-transparent tamper resistant tape that will be checked at each visit. The PTM device will 
be able to operate normally, but the screen or any data from the PTM will not be visible to the 
subject.
3.4.2
Randomization/Assignment to Study Drug
Each subject who is entered into the study will be assigned an enrollment number by the site, that 
consists of the two digit site number (##) and a subject number consisting of three-digits (XXX).
This number will be used for the entire duration of the trial.
For subjects who meet the criteria for randomization, a treatment group randomization code will 
be assigned to that subject number via an interactive web-based randomization system (IWRS).
The subject will then be randomized to either remain on the current dose of intrathecal
hydromorphone hydrochloride or will be titrated downward to a sub-therapeutic dose starting on
Day 84. The unblinded pump technician will have a unique user name and password to the IXRS 
(ie, web based randomization system) to allow them to access the treatment assignment.


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3.5
Study Drugs
3.5.1
Rationale for Doses and Dosing Regimen
3.5.1.1    Dose Conversion Period
Subjects entering the trial on a therapeutic dose of intrathecal hydromorphone hydrochloride may 
be converted directly to study medication without dose adjustment.
Subjects who will be converted from their current intrathecal morphine therapy to intrathecal 
hydromorphone hydrochloride according to the following scheme:
Subject Status on Morphine
Conversion 
Ratio
Dose ≤ 30 mg IT morphine and tolerating therapy 
well
1 : 6 1
Dose > 30 mg IT morphine or subject has 
significant side effects on morphine
1 : 12 2
1Conversion is based on mg-morphine equivalence such that for each 6 mg morphine sulfate the dose is 
converted to 1 mg hydromorphone hydrochloride.
2 Conversion is based on mg-morphine equivalence such that for each 12 mg morphine sulfate the dose is 
converted to 1 mg hydromorphone hydrochloride.
The subject should be contacted by telephone 24 hours after initiating study medication. If 
combinations are used in the previous intrathecal therapy, oral medications may be provided to 
replace the intrathecal combination regimen. However, for the duration of the CNS-HYD201US 
trial only hydromorphone hydrochloride may be used in the intrathecal pump as monotherapy.
Depending on the subjects starting dose on hydromorphone hydrochloride, either a 2 mg/mL or 
10 mg/mL formulation of hydromorphone hydrochloride for intrathecal injection may be used.
Subjects who are converted directly to a therapeutic dose of hydromorphone hydrochloride (ie,
direct conversion from previous treatment with hydromorphone, will start the study on Day 1 
(see Appendix A: Schedule of Study Procedures). For subjects that are converted to a lower dose 
based on the 1:12 conversion scheme for safety reasons, up to five (5) optional study visits (Days 
A, B, C, D and E) are permitted to allow dose titration to a therapeutic dose that is well tolerated.
These optional visit days may be from three (3) to seven (7) days apart. After the subject 
achieves a therapeutic dose of hydromorphone hydrochloride the procedures starting with Day 1 
of the study will be followed to ensure the subject is treated for the full 12 week period at a 
therapeutic dose of intrathecal hydromorphone hydrochloride.
3.5.1.2    12-Week Open-Label Treatment Phase
Subjects will start study Day 1 when they are determined to be at a therapeutic dose of 
intrathecal hydromorphone hydrochloride. Day 1 should be initiated after a direct conversion to 


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intrathecal hydromorphone based on a 1:6 morphine equivalence ratio, or if converted to a lower 
dose after a short titration period to achieve a therapeutic dose.
Dose adjustments thereafter will be allowed by adjusting the pump speed based on the following 
scheme:
Dose of Hydromorphone 
Hydrochloride IT
Maximum Dose 
Adjustment
0.1 to 0.5 mg/day
50%
> 0.5 mg/day
25%
Prior to a dose adjustment above 1 mg/day, the pump will be drained and refilled with 10 mg/mL 
hydromorphone hydrochloride undiluted and the pump speed will be adjusted to achieve the 
target dose.
During the switch to hydromorphone hydrochloride, oral opioid supplement is permitted up to a 
dose of 180 mg-equivalent morphine per day. Dose adjustments may continue until an optimal 
dose of intrathecal hydromorphone is achieved and the subject can be weaned off oral 
supplement as much as possible.
A maximum dose of 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any 
time during this study. For PTM dosing this maximum dose includes the patient activated doses 
that are allowed by the device programming. Subjects may be given oral supplemental 
medication up to a maximum of 180 mg-equivalent morphine per day, however, the objective of 
the trial during this period through Day 77 is to achieve an optimal dose of intrathecal 
hydromorphone hydrochloride and eliminate any oral supplement.
On Day 77 the pump should be refilled with intrathecal hydromorphone and any final 
adjustments made to the daily dose or programming. On Day 77, the subject will be given a 
remote monitoring device to measure VASPI scores twice daily in the morning (5:30 am to 
12:00 noon) and in the evening (6:00 pm to 11:45 pm). After Day 77 and during the randomized 
double-blind period there should be no dose adjustments other than those dictated by the protocol 
for subject on the control arm who are weaned off therapy. After Day 77, there should also be no 
changes to the pump programming for simple continuous, complex continuous with or without 
use of a PTM dosing regimens until after the completion of the trial.
Subjects discontinuing prior to randomization and not rolling over into the CNS-HYD202US 
trial, will have their follow up visit approximately 2 weeks after discontinuing the trial.
3.5.1.3    5-Week Randomized Double-Blind Period
On Day 84 subjects will be randomized to one of two groups. The criteria for randomization is 
defined as a an average VASPI score of 50 mm or less on a scale of 100 mm for the last 5 days 
with daily pain measurements prior to randomization on Day 84. The active group will remain at 


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their optimal dose of hydromorphone hydrochloride for the duration of the 5-week double-blind 
period. For those subjects randomized to be withdrawn from hydromorphone hydrochloride
therapy on Day 84, the pump speed will be adjusted to decrease the dose each 7 days (± 1 day), 
starting at a dose of 75%, 50%, 25%, 12.5% and approximately 0% of the dose at the time of 
randomization (See Appendix A, Table A- 2). For PTM dosing, the base continuous dose and the 
PTM dose would be decreased by the specified percentages above. The total maximum dose of 
10 mg/day will be the combined total of the decreased base dose and PTM dose.
To preserve the blind during the 5-week double-blind period, an Unblinded Pump Operator will 
be assigned at the site, who is independent from the investigator or other personnel that evaluate 
the subject’s condition. This Unblinded Pump Operator will manage all pump speed and dose 
adjustments. The group randomized to remain at a constant optimal dose and those randomized 
to the control group (titration group) will return to the site on the same schedule and receive the 
same treatment. Subjects, who are on the active dose group, will have mock dose adjustments.
Subjects that use a PTM device will also have tamper resistant tape applied to the display screen.
The tamper resistant tape will be checked at each site visit to ensure the subject has not viewed 
the PTM screen.
After randomization on Day 84, no further dose adjustments for intrathecal hydromorphone
hydrochloride dosing, other than those dictated by the protocol for the control (titration) group,
will be permitted until after the 5 week double-blind phase of this study. Subjects will be allowed 
up to 60 mg morphine-equivalence or oral opioid per day only for the purpose of managing
withdrawal symptoms after randomization. This oral opioid supplement is not intended to 
manage pain and should only be prescribed for management of withdrawal symptoms, if needed.
Other non-opioid medications or non-pharmacologic (ie, devices) interventions used to manage 
pain should be kept constant after randomization on Day 84.
Prior to rescue medication being administered, subjects will complete Day 119 study 
assessments, if possible. After confirming with the investigator that it is acceptable to take rescue 
medication, if a subject cannot return to the study site for assessments they will be instructed to 
complete a VASPI score using the remote monitoring device immediately prior to taking oral 
rescue medication. If the subject can return to the site, rescue may be performed by either oral 
medication being administered or by increasing the pump speed to achieve a therapeutic dose of 
hydromorphone hydrochloride, or both.
At the time of rescue the day, time and amount of rescue medication provided to address the 
intolerable pain will be recorded. Rescue may include providing oral or intravenous medication, 
as well as increasing the pump speed to titrate the subject back to an effective dose of intrathecal 
hydromorphone hydrochloride. Subjects who experience an increase on the average 5 day pain 
intensity score increase of 20 mm or more on a 100 mm scale over their baseline score on 
Days 77 to 83, will be considered a treatment failure regardless of receiving any rescue 
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3.5.1.4    12 Month Course of Treatment
Subjects that complete the 5-week randomized, controlled portion of this trial and those who are 
treatment failures or were dropped from the study prior to randomization may be able to continue 
on intrathecal hydromorphone hydrochloride therapy for an additional 12 months to obtain safety 
data with long term treatment. If these subjects qualify they may enroll in the CNS-HYD202US 
trial that will be ongoing in parallel with this study.
For those subjects randomized to hydromorphone hydrochloride in the CNS-HYD201US trial 
and then enter the CNS-HYD202US trial, their dose may be maintained at the dose used during 
the 5-Week randomization phase of the trial, or may be adjusted.
For subjects randomized to the titration group who had a significant downward dose adjustment 
in the CNS-HYD201US trial and then enter the CNS-HYD202US trial, the pump will be 
adjusted to titrate the subject back to the optimal dose of intrathecal hydromorphone
hydrochloride.
In all cases, the highest dose permitted in these trials will be 10 mg/day of intrathecal 
hydromorphone hydrochloride.
3.5.2
Dose Interruption
Unscheduled dose interruptions are not permitted on this clinical trial. Subjects who must 
experience a dose interruption will be discontinued from the trial.
3.6
Concomitant Medications
3.6.1
Prior and Concomitant Medications
Prior medications are defined as medications that were taken within 30 days prior to initial 
dosing with study drug. 
Concomitant medications are defined as medications taken any time after the start of dosing until 
the final visit. For concomitant medications being taken during the dosing period with intrathecal 
hydromorphone hydrochloride and the randomized withdraw, if the medication is needed long 
term the medication should be recorded as a concomitant medication and maintained at a 
constant dose during the trial.
There is inadequate systematic experience with the use of intrathecal hydromorphone
hydrochloride in combination with other medications to predict specific drug-drug interactions.
Interactions attributed to the combined use of intrathecal hydromorphone hydrochloride and 
other epidural drugs include hypotension and respiratory depression.


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3.6.2
Prohibited Concomitant Medications
During treatment with intrathecal hydromorphone hydrochloride, use of sedatives, hypnotics, 
phenothiazines, anesthetics, tranquilizers or other drugs that may induce CNS and respiratory 
depression should be assessed by the primary investigator and used with caution. For subjects 
who are on concomitant medications that may induce respiratory depression in combination with 
hydromorphone hydrochloride, the medical monitor should be consulted prior to enrollment.
Subjects will be instructed to avoid excessive alcohol consumption while on therapy.
Agonist/antagonist analgesics (ie, pentazocine, nalbuphine, butorphanol, and buprenorphine) 
should be administered with caution to a subject who has received or is receiving a course of 
therapy with a pure opioid agonist analgesic such as hydromorphone hydrochloride. In this 
situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone
hydrochloride and/or may precipitate withdrawal symptoms in these subjects.
Opioids can interact with drugs that increase the effects of serotonin (see Section 1.3.1). 
These include antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin 
and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine 
oxidase (MAO) inhibitors, mirtazapine, and trazodone; triptans (migraine medication); 5-HT3 
receptor antagonists (antiemetic drug); tramadol (analgesic drugs); linezolid (antibiotics); and 
intravenous methylene blue (antidote for methemoglobinemia). The interaction could cause a 
rare but potentially life-threatening condition called serotonin syndrome. All such medications 
should be administered with caution57.
3.7
Nonpharmacologic Interventions
Non-pharmacologic interventions for the management of pain are permitted in the 
CNS-HYD201US trial. After Day 77 no changes in the subject’s non-pharmacologic treatments 
for the management of pain are permitted until the end of the study.
3.8
Duration of Therapy
The duration of this trial is anticipated to include a 2 week screening period, an optional 5 weeks 
of titration, a 12 week chronic dosing period and 5 week double-blind period to assess efficacy.
Thus, subjects will remain in this trial for a total of up to 24 weeks if all 5 weeks of optional 
titration are needed.
3.9
Procedures for Monitoring Subject Compliance
Subjects will return to the clinic for scheduled visits and pump refills as specified in Appendix
A. Subjects who do not comply with the visit schedule may be discontinued from the study.


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4.0
STUDY POPULATION
Male or female subjects requiring intrathecal opioid treatment to manage severe intractable pain,
18 to 75 years of age.
4.1
Inclusion Criteria
For a subject to be eligible for this study, s/he must meet all of the following criteria: 
1. Subject must be at least 18 years of age and no more than 75 years old.
2. Clinically diagnosed with chronic pain for at least a 6-month period.
3. Subject is presently on intrathecal pain medication and has a SynchroMed II Implantable 
pump or meets clinical criteria for implantation of a SynchroMed II Implantable pump. 
Subjects who are naïve to intrathecal therapy, may be enrolled 2-weeks after pump 
implantation.
4. Subject agrees to sign a Pain Treatment Agreement (Narcotic Contract) limiting narcotic 
prescriptions to the study physician.
5. Subject must be cognitively intact and, in the opinion of the investigator, capable of 
participation in the trial.
6. Female subjects of child-bearing potential must agree to use a medically acceptable and 
effective double-barrier method of birth control.
7. Subjects with existing SynchroMed II Implantable pumps and are reasonably expected to
benefit from intrathecal opioid therapy.
8. Subjects who are capable of receiving an MRI with and without contrast or CT 
myelogram, if required by the study protocol.
9. Provides written Ethics Committee approved informed consent.
10. Willing to comply with all study procedures and requirements.
4.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from participation in the study:
1. Women who are pregnant or are breast-feeding.
2. Subjects who have participated in an investigational drug or device trial within 4 weeks 
prior to enrollment.
3. Subject has any known or suspected allergy to hydromorphone or to the materials of the 
infusion pump or intrathecal catheter.
4. Subject is scheduled for a pump or catheter replacement within 6 months of their 
enrollment into the trial.
5. Subject has a history of dependence and abuse of opioids, stimulants, alcohol, or 
benzodiazepines, as defined by DSM-IV criteria, within the past year (physical 
dependence on prescribed opioid analgesics is allowed but abuse of opioids according to 
DSM-IV is not permitted, ie, opioid addiction for recreational use).
6. Subjects who show signs of active systemic infection.


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7. Subjects with a metastatic cancer to the spinal canal or a known central nervous system 
contraindication to intrathecal therapy.
8. Subject has a condition requiring diathermy procedures.
9. Subject has a life expectancy of less than 12 months.
10. Subject cannot independently comprehend and participate in the required assessments, 
including responding to the VASPI, SF-MPQ, COWS, SOWS, BPI and PGIC 
measurement tools.
11. Subject is not considered to be medically or psychologically appropriate for pump 
implantation.
12. Subjects who are unable or unwilling to return to all of the required follow-up visits.
13. Subjects with active implanted devices such as pacemakers, defibrillators, and cochlear 
implants or other medical device use, if in the opinion of the investigator the device 
would interfere with ability to perform an MRI or CT myelogram.
14. As a result of medical review and physical examination, the Investigator considers the 
subject unfit for the study.
15. Pain located above the shoulders in the head or neck region (e.g. trigeminal neuralgia), 
central pain syndromes or any other condition in which it is judged to be unlikely that 
the subject would benefit from intrathecal administration of the drug product.
16. Subjects who have previously been unresponsive to intrathecal hydromorphone therapy. 
5.0
SAFETY ASSESSMENTS
5.1
Collection of Adverse Events Data
Data regarding treatment-emergent AEs will be collected in this study. Treatment-emergent AEs 
are events that are not present at baseline, or if present at baseline, have worsened in severity. 
AEs will be assessed at each study visit from the time of study drug administration through the 
final visit. AEs assessed by the Investigator as related to study drug and “ongoing” at the final 
scheduled study visit will be monitored by the Investigator until resolved or stabilized.
Each subject will be observed and queried by the Investigator or his/her designee at each study 
visit for any continuing AEs or new AEs since the previous visit. If an AE occurs between study 
visits, regardless of causal relationship to study drug and in the opinion of the Investigator the 
subject requires a study visit for full evaluation, the subject will be asked to return to the site for 
an unscheduled visit. 
Any AE reported by the subject or noted by the Investigator or his/her designee will be recorded.
The following information will be recorded for each AE: description of the event, date and time 
of onset, date and time of resolution, severity, causal relationship to study drug, outcome, action 
taken with the study drug and any treatment given.


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All abnormal changes from baseline in physical examination findings or vital signs will be 
collected, graded with regards to severity or clinical significance, assessed for causal relationship 
and will be recorded.
5.2
Physical Examinations and Medical History
5.2.1
Complete Physical Examination
The Investigator or designee will perform and record a complete physical examination at 
screening, Day 84, Day 119 and final study visit. Assessments of height, weight, calculation of 
body surface area (BSA), and vital signs will be recorded. Any underlying medical condition will 
be recorded as ongoing baseline events for future assessment of adverse events or serious 
adverse events. Only adverse changes from this baseline condition will be considered adverse 
events or serious adverse events.
5.2.2
Medical History, Pump Implantation and Surgical History
A medical history will be obtained at screening. Medical history will include demographic data 
(age, gender, race/ethnicity, etc.). In addition to general medical conditions, specific information 
relative to the underlying disease that resulted in severe intractable pain requiring an intrathecal 
pump will be obtained and recorded:

Underlying disease, injury or condition resulting in intractable pain, date of initial 
diagnosis, and prior treatments.

Date of implantation of an intrathecal pump. If a previous pump was removed and a new
pump has been implanted, the date of each implantation and reason for removal is 
requested.

Date of surgical interventions for treatment of intractable pain.

History of prior opioid use (oral, transdermal or intravenous) prior to implantation of the 
pump.

Other significant medical history.
5.3
Clinical Laboratory Testing and ECGs
Clinical laboratory testing (CBC, CMP, and urinalysis) and ECGs are performed only at 
screening for the purpose of determining the subject’s eligibility for the study. Results will be 
recorded as normal, abnormal or abnormal clinically significant. Raw data will be kept as source 
documents at the site and not entered into the database.
Women of childbearing potential will have urine pregnancy testing completed at screening 
and/or baseline results will be recorded.


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5.4
Vital Signs
Systolic and diastolic blood pressure, radial pulse, breathing rate, temperature, and weight will 
be obtained and recorded at screening, baseline (if a different visit) and each study visit.
5.5
Documentation of Concomitant Medications
Details regarding the name, indication, dose, route of administration, and frequency of all 
prescription medications taken within the past 30-days or while on study will be recorded.
6.0
PHARMACOKINETICS
Blood samples for determination of the steady state plasma pharmacokinetics (PK) of 
hydromorphone following continuous infusion will be collected during the study. The total 
volume of blood drawn for PK analysis is 24 mL over the course of the study. Each PK sample 
will be 6 mL of blood collected into a standard plasma sample tube and centrifuged to obtain at 
least 3 mL of plasma. The sample will be separated into two 1.5 mL aliquots and frozen to 
< -20°C until shipment to the central testing facility.
Blood will be collected for analysis of hydromorphone concentration in plasma prior to dosing
with any daily oral medications (ie, other oral opioids permitted in the protocol) on Day 14, Days
56, 77 and Day 84.
7.0
PHARMACODYNAMICS
Other than pain evaluation, no pharmacodynamic assessments are planned during this trial.
8.0
EFFICACY
The primary efficacy endpoint is the proportion of subjects who are treatment failures during the 
double-blind randomized withdrawal period. The definition of a treatment failure for this trial is:
Treatment Failure Criteria: After randomization, a treatment failure will be defined by the 
following criteria:
1. A subject who experience an increase of 20 mm or more above the baseline value on a 
100 mm VASPI based on the average of 5 days, or
2. A subjects who experience intolerable pain that in the opinion of the investigator requires 
intervention (ie, rescue), or
3. Any subject who has other interventions for pain that violate the protocol from Day 84 to 
119 that includes:


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a.Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent to 
manage withdrawal symptoms, or
b.Has a change in non-opioid oral prescription medications or non-pharmacological 
treatments being administered for the management of pain.
Note: A subject who does not have sufficient data for evaluation, drops out for any other 
reasons that are not listed above or who experiences withdrawal syndrome as identified by 
COWS > 12 during the double-blind treatment phase will not be classified as a treatment 
failure in the primary efficacy analysis.
9.0
STUDY VISITS
Refer to Appendix A: Schedule of Study Procedures
The Schedule of Study Procedures includes two separate tables:

Table A- 1: Schedule of Study Procedures: Screening and Chronic Dosing Phase to Day
56.

Table A- 2: Schedule of Study Procedures: Final 7 Days of Continuous Dosing, 
Randomized Withdrawal and Efficacy Evaluation Period.
9.1
Screening
The Investigator or his/her approved designee must explain the nature of the study protocol and 
associated risks to the potential study participant. The potential participant must be allowed to 
review the study information and to ask questions before being asked to sign the Informed 
Consent Form. Written informed consent must be provided by the potential study participant or 
legal guardian prior to initiation of any screening evaluations or other study-related procedures. 
The signature date and the name of the individual at the site who obtained the informed consent 
will be recorded in the subject’s medical record. 
After written informed consent is obtained, the subject will be assigned a three-digit number
screening number (SXXX) and will undergo the designated screening procedures listed in 
Appendix A within 14 days prior to study drug administration. The Investigator will assess the 
results of these screening evaluations to determine eligibility for entry into the study according to 
the inclusion/exclusion criteria listed in Section 4.0. Subjects who delay participation in the trial 
for any reason or fall outside the screening window before dosing, may be rescreened and will 
retain their same screening number. For subjects who fail an entry criteria, rescreening may be 
permitted, retaining the original screening number, with the approval of the Medical Monitor 
prior to enrollment of the subject.


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9.2
Baseline Evaluations
If a subject is determined to be eligible for participation in the study they will undergo baseline 
assessments prior to drug administration. Baseline assessments will be conducted according to 
the procedures outlined in Appendix A: Schedule of Study Procedures
Note that the Baseline, Screening and the first day of dosing may be combined at one visit.
9.3
Dose Conversion and Optional Titration Period
Subjects entering the trial on a therapeutic dose of intrathecal hydromorphone hydrochloride may 
be converted directly to study medication without dose adjustment.
Subjects who will be converted from their current intrathecal morphine therapy to intrathecal 
hydromorphone hydrochloride according to the following scheme:
Subject Status on Morphine
Conversion 
Ratio
Dose ≤ 30 mg IT morphine and tolerating therapy 
well
1 : 6a
Dose > 30 mg IT morphine or subject has 
significant side effects on morphine
1 : 12b
aConversion is based on mg-morphine equivalence such that for each 6 mg morphine sulfate the dose is 
converted to 1 mg hydromorphone hydrochloride.
bConversion is based on mg-morphine equivalence such that for each 12 mg morphine sulfate the dose is 
converted to 1 mg hydromorphone hydrochloride.
The conversion will take place by removing the current product in the pump and then replacing 
the contents with hydromorphone hydrochloride for intrathecal injection. At the discretion of the 
investigator the pump reservoir may be rinsed with preservative free sterile saline or the study 
drug (hydromorphone hydrochloride for injection). The subject should be contacted by telephone 
24 hours after initiating study medication. If combinations are used in the previous intrathecal 
therapy, oral medications may be provided to replace the intrathecal combination regimen. 
However, for the duration of the CNS-HYD201US trial only hydromorphone hydrochloride may 
be used in the intrathecal pump as monotherapy. Depending on the subjects starting dose on 
hydromorphone hydrochloride, either a 2 mg/mL or 10 mg/mL formulation of hydromorphone 
hydrochloride for intrathecal injection may be used.
Subjects who are converted directly to a therapeutic dose of hydromorphone hydrochloride (ie,
direct conversion from previous treatment with hydromorphone, or a 1:6 conversion from a 
therapeutic dose of converted to a lower dose based on the 1:12 conversion scheme for safety 
reasons, up to five (5) optional study visits (Days A, B, C, D and E) are permitted to allow dose 
titration to a therapeutic dose that is well tolerated. These optional visit days may be from three 
(3) to seven (7) days apart. After the subject achieves a therapeutic dose of hydromorphone 


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hydrochloride the procedures starting with Day 1 of the study will be followed to ensure the 
subject is treated for the full 12 week period at a therapeutic dose of intrathecal hydromorphone 
hydrochloride.
9.4
Continuous Dosing Period (Day 1 to Day 83)
Once a subject is at a therapeutic dose of hydromorphone hydrochloride for intrathecal injection, 
study Day 1 will be initiated. This may be directly after conversion to hydromorphone 
hydrochloride if at a therapeutically equivalent dose to their prior therapy or after dose titration 
as needed to achieve a therapeutic dose.
Further dose adjustments during the 12-week continuous dosing period are permitted with each 
scheduled visit (Appendix A, Table A- 2) to achieve the optimal treatment of pain. Dose 
adjustments will be allowed by adjusting the pump speed based on the following scheme:
Dose of Hydromorphone 
Hydrochloride IT
Maximum Dose 
Adjustment
0.1 to 0.5 mg/day
50 %
> 0.5 mg/day
25 %
Unscheduled visits are permitted if deemed necessary to manage the subjects condition with 
notification to the study Medical Monitor.
A maximum dose of hydromorphone hydrochloride of 10 mg/day is permitted in this trial.
Subjects may be given up to 180 mg-equivalent morphine per day up to Day 77 to help manage 
break through pain or withdrawal until the subject is titrated to an optimal dose. Ideally, the 
subject should be weaned of all oral medications as the optimal dose of hydromorphone 
hydrochloride is achieved. 
On Day 77 the pump should be refilled with intrathecal hydromorphone hydrochloride and any 
final adjustments made to the daily dose or programming. On Day 77, the subject will be given a 
remote monitoring device to measure VASPI scores twice daily in the morning (5:30 am to 
12:00 noon) and in the evening (6:00 pm to 11:45 pm). After Day 77 and during the randomized 
double-blind period there should be no dose adjustments other than those dictated by the protocol 
for subject on the control arm who are weaned off therapy. After Day 77, there should also be no 
changes to the pump programming for simple continuous, complex continuous or PTM dosing 
regimens until after the completion of the trial.
During the last 7 days of the continuous dosing period (Days 77 to 83) the subject should be off 
any oral opioid supplement and no new or changes to prescription medications for pain, as well 
as no new or change in non-pharmacologic interventions for pain are allowed.


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At each study interim visit subjects will be assessed for AEs and clinical signs or symptoms of 
an inflammatory granuloma. If an AE is reported, a targeted physical exam will be conducted to 
evaluate the severity and causality of the event (See Appendix A).
If interim visits more frequent than scheduled in Appendix A, Table A- 1, are necessary due to the 
need to adjust dose to optimize the pain relief or reduce side effects, the site may schedule the 
extra visit, but is asked to notify the Medical Monitor.
All visit dates during the dose titration and stabilization period are to be conducted within 2 days 
of the scheduled date (ie, ± 2 days).
9.5
Randomized Withdrawal and Efficacy Evaluation Period (Day 84 to Day 119)
On Day 84 subjects will be randomized to one of two groups. The active group will remain at 
their optimal dose of hydromorphone hydrochloride for the duration of the 5-week double-blind 
period. The group randomized to be withdrawn from therapy will have their dose of intrathecal 
hydromorphone hydrochloride titrated downward with a dose reduction each 7 days. Dose 
reductions will be to 75%, 50%, 25%, 12.5%, and approximately 0% (ie, minimum pump speed 
or shipping mode) of the initial dose on each successive dose reduction (See Appendix A, Table
A- 2).
To preserve the blind during the 5-week double-blind period, a person at the site, who is 
independent from the investigator or other personnel that evaluate the subjects condition, will 
manage pump speed adjustments. Both groups randomized to remain at a constant optimal dose 
and those randomized to withdraw will return to the site on the same schedule and receive the 
same treatment. Subjects who are on the active optimal dose group, will have mock dose 
adjustments. Subjects who utilize a PTM device will have the display screen covered with 
tamper resistant tape to avoid seeing the pump refill date alarm.
After randomization on Day 84, no further dose adjustments will be permitted other than those 
defined by the protocol for the control (titration) group, until after the 5 week double-blind phase 
of this study. Subjects will be allowed up to 60 mg morphine-equivalence of oral opioid per day
only for the purpose of managing withdrawal symptoms after randomization. During the 5-week 
period after randomization, VASPI assessments will be conducted twice each day using a remote 
data collection device. COWS, SOWS, BPI and PGIC assessments will be conducted at each 
scheduled visit. 
Prior to rescue medication being administered, subjects will complete Day 119 study 
assessments, if possible. After confirming with the investigator that it is acceptable to take rescue 
medication, if a subject cannot return to the study site for assessments they will be instructed to 
complete the VASPI assessment on the remote monitoring device immediately prior to taking 
oral rescue medication. If the subject can return to the site, rescue may be performed by either 
oral medication being administered or by increasing the pump speed to achieve a therapeutic 
dose of hydromorphone hydrochloride, or both.


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The day, time and amount of rescue medication provided to address the intolerable pain will be 
recorded. Rescue may include providing oral or intravenous medication, as well as increasing the 
pump speed to titrate the subject back to an effective dose of intrathecal hydromorphone
hydrochloride. Subjects who experience an average 5 day pain intensity score increase of 20 mm 
or more on a 100 mm scale over their baseline score, will be considered a treatment failure 
regardless of experiencing any intolerable pain.
At each study interim visit subjects will be assessed for AEs and clinical signs or symptoms of 
an inflammatory granuloma. If an AE is reported, a targeted physical exam will be conducted to 
evaluate the severity and causality of the event (See Appendix A).
All visit dates during the randomized withdrawal period are to be conducted within 1 day of the 
scheduled date (ie, ± 1 day).
9.6
Long-Term Follow Up (CNS-HYD202US Safety)
Subjects who complete the CNS-HYD201US trial are allowed to enroll in the CNS-HYD202US 
study and continue on hydromorphone hydrochloride therapy for an additional 12 months.
A subject who is dropped from the study prior to randomization or a treatment failure during the 
double-blind randomized withdrawal period will be allowed to enroll in the CNS HYD202US 
study if the PI believes that the subject meets the study selection criteria and would benefit from
participation in the study. For subjects who were stable during the double-blind randomized 
withdrawal period, the same infusion rate and daily dose may be maintained or a dose adjustment 
implemented at the discretion of the investigator. If the subject experienced significant increases 
in pain and required rescue medication, the subject should be re-titrated onto intrathecal 
hydromorphone hydrochloride and slowly withdrawn from any oral opioid medications. All 
subjects may have their dose of intrathecal hydromorphone hydrochloride adjusted during this
period as necessary to obtain optimal pain relief, provided the dose does not exceed 10 mg/day.
Oral opioid supplemental medication may be prescribed as necessary and appropriate according 
to the practice of medicine. Other FDA approved non-opioid oral pain medications are permitted 
during this period in accordance with their marketed product labeling. 
Study procedures and assessments for the long term follow up safety study should be followed 
according to protocol CNS-HYD202US. Pump refills during this period are conducted as needed 
to maintain the appropriate volume of product in the pump and maintain the subject dosing.


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9.7
Final Visit
Subjects who do not enter the CNS-HYD202US long-term safety trial will return to the 
investigational site for the final visit 2 weeks (± 4 days) after discontinuation from the trial.
At the final study visit subjects will be assessed for AEs and clinical signs or symptoms of an 
inflammatory granuloma as well as other procedures according to Appendix A, Table A- 2.
Also during the final visit the investigator will remove all study drug from the subjects pump and 
will continue the subjects normal standard of care. 
10.0 PREMATURE DISCONTINUATION FROM STUDY
A premature discontinuation from study will occur when a subject who signed informed consent 
ceases participation in this study, regardless of circumstances, prior to completion of the defined 
study period. Subjects can be prematurely discontinued from the study for one of the following 
reasons: 

Failure to meet inclusion/exclusion criteria before receiving first dose of study drug has 
been administered.

Noncompliance with study procedures and visit schedules.

Death.

Significant safety event that does not resolve within 7 days of lowering the dose or other 
clinical interventions.

Lost to follow-up after every attempt has been made to contact the subject including 
sending a registered letter.

Subject withdraws consent.
The reason for the discontinuation should be recorded.
The Principal Investigator and the Institutional Review Board/Ethics Committee (IRB/EC) 
reserve the right to prematurely terminate the study in the interest of subject safety and welfare. 
The Sponsor reserves the right to prematurely terminate the study at any time for administrative 
reasons.
11.0 PREMATURE DISCONTINUATION FROM STUDY DRUG
The Investigator will continue to monitor subjects who have discontinued prematurely from 
study drug due to an AE (serious and non-serious) until resolution or stabilization of the AE. 
The Investigator must complete all applicable electronic CRF pages for subjects who discontinue 
study drug prematurely. Final visit procedures (See Appendix A, Table A- 2) should be 
conducted for any subject who discontinues study drug prematurely.


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If a subject is discontinued from therapy, study medication should be removed from the pump 
and the subject placed on standard of care therapy at the discretion of the investigator.
12.0 PRODUCT SPECIFICATIONS
12.1
Description
Hydromorphone hydrochloride for injection (intrathecal) 2 mg/mL and 10 mg/mL is provided in 
single use vials of 40,000 mcg per 20 mL or 200,000 mcg per 20 mL for intrathecal 
administration only.
The drug product is manufactured under current Good Manufacturing Practices (cGMP) at DSM 
Pharmaceuticals, Inc., or at Patheon Manufacturing Services LLC, contract manufacturing 
facilities that have undergone FDA inspection.
12.2
Formulation, Packaging, and Labeling
Hydromorphone hydrochloride for injection (intrathecal) 2 mg/mL and 10 mg/mL will be 
supplied in single use vials and contains hydromorphone hydrochloride and water. Single use 
vials will be packaged in shipping containers for shipment to the clinical sites.
Study drug vial will be affixed with a single label panel containing the following information:
Hydromorphone Hydrochloride Injection (Intrathecal)
40,000 mcg/20 mL (2,000 mcg/mL) or 200,000 mcg/20 mL (10,000 mcg/mL)
Lot Number: XXXXXX
Manufacturing Date: MM-DD-YYYY
Store at Room Temperature (15° to 30℃)
Protect from light – store in package until ready to use
Caution: New Drug – Limited by U.S. Federal Law to Investigational Use
Manufactured for CNS Therapeutics, Inc.
12.3
Receipt, Storage and Stability of Hydromorphone Intrathecal
Hydromorphone hydrochloride for injection (intrathecal) vials will be packaged in boxes for 
shipment to investigational sites. Excursions permitted to 4° to 30C (39° to 86 °F), and after 
receipt should be stored at 15° to 30°C (59° to 86°F) until use.
12.4
Preparation and Administration of Study Drug
There is no manipulation or preparation of study drug other than filling into the SynchroMed® II
Infusion Pump according to the manufacturer’s instructions.


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12.5
Ordering and Distribution of Study Drug
Study drug may be requested by submission of a medication request form. The form may be 
submitted to the Sponsor or designee by facsimile or electronic mail PDF as per the instructions 
on the drug ordering form.
12.6
Accountability of Study Drugs
All study drugs received, dispensed, and returned must be accounted for in the study drug 
Dispensing Log, including:

Subject number and initials.

Date study drug was dispensed.

Quantity dispensed.

Quantity returned.

Amount wasted (if applicable).
All study drug received and dispensed by the Investigator will be inventoried and accounted for 
throughout the study by the clinical monitors. The study drug must be stored in a restricted area 
with limited access. Contents of the study drug containers must not be combined.
The Investigator must maintain an accurate, up to date Dispensing Log for all study drugs 
supplied by the Sponsor. Study drug dispensed for all subjects must be recorded on the Drug 
Accountability Form. The study drug Dispensing Log and remaining drug inventory will be 
verified at each monitoring visit by the Sponsor-designated clinical monitor.
The study drug supplied for this study is for use only in subjects properly consented and enrolled 
into this protocol. Study drugs must be kept in a secure location physically separated from 
standard clinic or office drug supplies.
Please note that hydromorphone hydrochloride is a Schedule II DEA restricted drug and as such 
all appropriate DEA procedures for handling and accountability of the investigational drug 
product must be complied with during this trial. All sites must be registered and licensed to 
manage Schedule II drugs by the DEA. See the Investigators Brochure for more detail about 
management of scheduled opioid products.
13.0 SAFETY MONITORING AND ADVERSE EVENTS
13.1
Adverse Events
Data regarding treatment-emergent AEs will be collected in this study. Treatment-emergent AEs 
are events that are not present at baseline, or if present at baseline, have worsened in severity.


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The descriptions and grading scales found in the Common Terminology Criteria for Adverse 
Events (CTCAE) v 4.03 will be used for AE reporting. A copy of the CTCAE v 4.03 is provided 
in Appendix B.
The medical monitor and contact information for this study are presented below:
Jean T. (Toby) Barbey, MD
Medical Director, 
Social & Scientific 
Systems, Inc.
Silver Spring, MD
20910
Office: 301-628-3316
Mobile: 202-251-6523
E-mail: jbarbey@s-3.com
Definition of Adverse Events and Adverse Drug Reactions:
Adverse events will be classified according to the most recent FDA definitions and in a manner 
consistent with ICH guidelines. As such the following definitions will be used:
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product (IP) or other protocol-imposed 
intervention, regardless of attribution. An AE may include intercurrent illnesses or injuries that 
represent an exacerbation (increase in frequency, severity, or specificity) of pre-existing 
conditions (e.g., worsening of asthma). A laboratory abnormality will be reported on the 
“Adverse Event” case report form only if it is associated with clinical sequelae or requires 
therapeutic intervention. Whenever possible, it is preferable to record a diagnosis as the AE term 
rather than a series of symptoms relating to a diagnosis. AEs will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.
The reporting period for nonserious AEs starts after the first administration of study drug and 
ends after discontinuation of study medication.
SAEs must be followed until resolution by the PI, even if this extends beyond the study-reporting 
period. Resolution is defined as the return to baseline status or stabilization of the condition with 
the expectation that it will remain chronic.
The investigator will assess AEs for severity, for relationship to Investigational Product (IP), and 
as to whether the event meets one or more of the definitions of an SAE. The investigator will 
determine the relationship of an AE to the IP and will record it on the source documents and AE 
CRF, using the categories defined below.


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Table 13-1
Causality Categories for AE Descriptions
Causality 
Category
Description
Unlikely
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. For the purpose of this protocol, the term 
unlikely will be considered not related to study medication and an “Adverse 
Event”.
Possible
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administrations of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information on 
drug withdrawal may be lacking or unclear. For the purpose of this protocol 
an event that has possible relationship to study medication will be defined as 
a “Suspected Adverse Drug Reaction”.
Probable
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal. For the purpose of this 
protocol an event that has probable relationship to study medication will be 
defined as a “Adverse Drug Reaction”. 
In order to classify adverse events and diseases, preferred terms will be assigned by the sponsor 
or its designee to the original terms using MedDRA. CTCAE is provided in Appendix B.


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Table 13–2
Severity Assessment Terminology for Reporting Adverse Events 
(CTCAE v4.03)
Description of Event Intensity
Grade
Mild
1
Moderate
2
Severe
3
Life-threatening or disabling*
4
Death related to AE*
5
*must be reported as an SAE
For those AEs that are not described on the CTCAE v 4.03, such AEs will be graded according 
to the same scale as defined above.
13.2
Serious Adverse Events
According to the ICH Guidelines for Good Clinical Practice (E6), an SAE is any untoward 
medical occurrence during the course of a clinical investigation that is characterized by one or 
more of the following:

Results in death.

Is life-threatening.

Requires nonscheduled (not routine or planned) in-subject hospitalization or prolongation 
of existing hospitalization.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Important medical events.
Although not a formal SAE, exposure to study drug during pregnancy, even if no AE is reported 
in the mother, should be reported within 24 hours as an SAE.
For subjects who are maintained in the hospital for scheduled observation or procedures related 
to the pump, and are not due to SAEs, the hospitalization will not be considered an SAE. Please 
contact the Medical Monitor with any questions on the definition of a routine event or scheduled 
hospitalization and if this event should be recorded as an SAE or will be considered routine 
standard of care.


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13.2.1 Reporting Requirements for Serious Adverse Events
Initial Reporting
SAEs (based on FDA/ICH definition of an SAE) require immediate reporting to Mallinckrodt or 
designated representative. 
For all fatal or life-threatening events, the investigator(s) or designee must report information 
within 24 hours to the Medical Monitor at 334-868-3111.
For all SAEs, the investigator(s) or designee must complete the SAE report form with the 
minimum information required by FDA and ICH and fax it to Mallinckrodt Pharmacovigilance 
at 314-654-5759 within 24 hours of first knowledge of the event even if the experience does not 
appear to be related to the study drug. 
The investigator(s) or designee will receive acknowledgement of receipt of the SAE report form 
from Mallinckrodt.
Should the investigator(s) or designee have any difficulty in sending the SAE report, they may 
contact Mallinckrodt Pharmacovigilance at 1-800-778-7898 (24 hour call center) or email: 
globalpv@mallinckrodt.com.
If there is any doubt about whether the information constitutes an SAE, the information is to be 
treated as an SAE.
Follow Up Reporting 
The investigator(s) or designee must complete an SAE report form for all follow-up information 
received and fax it to the sponsor 314-654-5759 within 24 hours of receipt of additional or 
updated information (eg, detailed written descriptions that include copies of relevant subject 
records, autopsy reports and other supporting documents). The investigator(s) or designee will 
receive acknowledgement of receipt for each SAE report form from Mallinckrodt.
The investigator(s) or designee is required to report immediately unexpected SAEs to the 
responsible IRB/IEC. 
All adverse events (serious and non-serious) occurring in subjects from the time of informed 
consent through the completion of the follow-up telephone call will be documented as an AE in 
the source and in the eCRF. All fields on the AE eCRF page should be completed for each event 
with a full description of the event and date and time of onset and resolution. The investigator 
must follow up on all AEs and SAEs until the events have subsided, until values return to within 
the acceptable range, the investigator determines that follow-up is no longer necessary, or the 
subject is referred to a nonstudy physician.
The sponsor will report SAEs to the FDA and investigators according to local regulations.


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Table 13–3
Reporting Requirements for Adverse Events
REPORTING REQUIREMENTS FOR ADVERSE EVENTS
Seriousness
Reporting Time
Type of Report
ALL SERIOUS
Within 24 hours
Initial report on the SAE form
Appropriate eCRF
Within 24 hours of receipt of follow-up 
information
Follow up/final report on the SAE 
form
NON-SERIOUS
Per case report form submission 
procedure
Appropriate eCRF
Table 13–4
Contact Information for SAE Reporting
Contact Information For SAE Reporting
Mallinckrodt Global Pharmacovigilance:
Office Fax: 
+1-314-654-5759
24-Hour Call Center
Telephone:
+1-800-778-7898
Email:
GlobalPV@mallinckrodt.com
13.2.2 Recording of Serious Adverse Events
All SAE information must be recorded on the SAE form provided by the Sponsor. Additional 
follow-up information (e.g., test results, autopsy, and discharge summary) may be requested to 
supplement the SAE report form and can be attached as de-identified records. A copy of all 
initial and follow-up reports must be filed with the subject’s medical records.
14.0 STATISTICAL CONSIDERATIONS
14.1
Sample Size Determination
Approximately 150 subjects will be enrolled at up to thirty (30) US investigative sites to obtain 
approximately 80 subjects who qualify for randomization into the double-blind period on Day 
84. This enrollment is based on a combined drop out and treatment failure (ie, > 50 mm on a 
100 mm VASPI score for the last 5 days with non-missing data prior to the double-blind period) 
rate of approximately 45%.
During the double-blind period, the true treatment failure rate in the hydromorphone 
hydrochloride arm is assumed to be at most 20%. Based on a two-sided, two-sample comparison 


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of proportions at the alpha = 0.05 level of significance, a sample size of 80 subjects (40 per arm) 
will provide greater than 90% power to detect an increase in the treatment failure rate of 35% (ie,
the control group who will have their dose titrated downward has a failure rate of 55%).
14.2
Analysis Data Sets
The ITT population includes all subjects who are randomized on Day 84 to either the active or 
control group in the double-blind randomized withdrawal portion of this study and receive at 
least one day of hydromorphone hydrochloride intrathecal treatment during the randomization 
period. All efficacy analyses will be carried out using the ITT population. In all efficacy 
analyses, subjects will be included in the group based on the treatment to which they were 
randomized.
The Safety population includes all subjects who have study medication loaded into their 
intrathecal pump (ie, any exposure to study medication). Safety analyses will be carried out using 
the Safety population. In all safety analyses, subjects will be included in the group based on the 
treatment they received (ie, randomized withdrawal or same dose hydromorphone continuation). 
Subjects who do not reach the point of randomization will be included in the overall column 
only.
14.3
Primary Efficacy Analysis
The primary efficacy endpoint is the treatment failure rate during the 5-week randomized 
double-blind period. After randomization, a treatment failure will be defined by the following 
criteria:
1. Any subject who experiences an increase of 20 mm or more above the baseline value on a 
100 mm VASPI based on the average of 5 days, or
2. Any subject who experiences intolerable pain that in the opinion of the investigator 
requires intervention (ie, rescue), or
3. Any subject who has other interventions for pain that violate the protocol from Day 84 to 
119 that includes:
a.
Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent to 
manage withdrawal symptoms, or
b. Has a change in non-opioid oral prescription medications or non-pharmacological 
treatments being administered for the management of pain.
Note: A subject who does not have sufficient data for evaluation, drops out for any other reasons 
that are not listed above or who experiences withdrawal syndrome as identified by COWS > 12 
during the double-blind treatment phase will not be classified as a treatment failure in the 
primary efficacy analysis.
As discussed in the National Research Council (2010, page 24) report on missing data, the 
estimand is the difference in outcome improvement in tolerators. Because the primary endpoint 


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is defined as a failure rate, and because any subject who cannot be defined as a “failure” is a 
treatment ”success”, the use of this endpoint in a randomized withdrawal study minimizes 
missing data (56). 
The treatment failure rates in the hydromorphone hydrochloride and control groups will be 
compared using Pearson’s chi-square test (two-sided) at the alpha = 0.05 level of significance.
14.4
Secondary Analyses
The change from baseline to week 5 in the BPI will be analyzed using an ANCOVA model with 
treatment group as a factor and the baseline BPI as a covariate. Other quantitative secondary 
endpoints will also be analyzed using this same type of ANCOVA model.
The distributions of time to rescue will be summarized in each treatment group using the Kaplan-
Meier method. The two groups will be compared using the log rank test.
The PGIC will be analyzed using the Cochran-Mantel-Haenszel mean score test (using equally 
spaced scores).
All secondary analyses will be carried out using two-sided tests at the 5% level of significance.
14.5
Safety
Safety data will be presented as summary and descriptive statistics, and will be provided for 
actual values and change from baseline values for vital signs 
The incidence and severity of AEs reported during the study and their relationship to study drug 
will be tabulated. AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™) and the CTCAE v 4.03, and will be presented by body system and preferred term. 
Particular attention will be paid to potential or confirmed granulomas and the outcome of these 
events will be followed to resolution.
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior and 
concomitant medications by therapeutic class and preferred term. Prior and concomitant 
medication usage will be summarized by the number and percentage of subjects receiving each 
medication within each therapeutic class by dose cohort.
15.0 DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE
15.1
Data Collection and Reporting
An electronic CRF (ie, Electronic Data Capture (EDC) system) will be completed for each 
subject who is assigned a study number, signs and dates the study-approved ICF, and receives at 
least one dose of study drug. For all entries into the EDC that are not source electronic data, the 


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data entries must be supported by original source documentation (e.g., laboratory reports, 
medical records) maintained at the investigational site. 
A paper CRF page will be used by the Unblinded Pump Operator to record dose administration 
information during Days 84 to 119. This CRF page will be held at the site and collected after the 
subject has completed the trial for manual entry into the database.
The Investigator will make all safety assessments (AEs, vital signs, and results from physical 
examinations) on an ongoing basis. The Investigator is required to review all entries entered into
the EDC and electronically sign at appropriate time intervals.
15.2
Study Monitoring
All aspects of the study will be monitored carefully by the Sponsor’s designees with respect to 
current Good Clinical Practice and Standard Operating Procedures for compliance with 
applicable government regulations. It is the responsibility of the Investigator to provide all study 
records, including EDC (CRFs), source documents, etc., for review and inspection by the clinical 
monitor.
All EDC (CRFs) will be 100% source verified against corresponding source documentation (e.g., 
office and clinical laboratory records) for each subject. Clinical monitors will evaluate 
periodically the progress of the study, including the verification of appropriate consent form 
procedures, review of drug accountability and preparation procedures, adherence to dosing 
procedures, and the verification of the accuracy and completeness of EDC (CRFs). Clinical 
monitors will also ensure that all protocol requirements, applicable FDA regulations, other 
requirements, and Investigator’s obligations are being fulfilled.
Paper CRFs will not be monitored by the blinded clinical monitor during routine monitoring 
visits. The CRF pages will be reviewed and confirmed to be accurate by a central unblinded 
monitor not involved in the conduct of the clinical trial. This central unblinded monitor will issue 
any queries necessary. The blinded clinical monitor will not review paper CRF pages until the 
subject completed the study.
15.3
Data Disclosure and Subject Confidentiality
Subject medical information obtained as a result of this study is considered confidential. 
Disclosure to third parties other than those noted below is prohibited. All reports and 
communications relating to subjects in this study will identify each subject only by their initials 
and number. Medical information resulting from a subject’s participation in this study may be 
given to the subject’s personal physician or to the appropriate medical personnel responsible for 
the subject’s welfare. Data generated as a result of this study are to be available for inspection on 
request by FDA or other government regulatory agency auditors, the Sponsor, the Sponsor-
assigned clinical monitor (or designee), and the IRB/EC.


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All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by a coded number to maintain subject confidentiality. All records will be maintained
in lockable file cabinets. All computer entry and networking programs will be identifiable only 
by coded numbers. Clinical information will not be released without written permission from the 
subject, except as necessary for monitoring by the IRB, the FDA, or representatives of the study 
Sponsor. 
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports, made or developed by the Investigator(s) as a result of 
conducting this study shall be promptly disclosed to the Sponsor and shall be the sole property of 
the Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing.
The results of this study will be published under the direction of the Sponsor. Results will not be 
published without prior review and approval by the Sponsor.
16.0 PROTECTION OF HUMAN SUBJECTS
16.1
Declaration of Helsinki
The study will be conducted in accordance with the Declaration of Helsinki (1964) including all 
amendments up to and including the South Africa revision (1996).
16.2
Institutional Review Board/Ethics Committee
The Investigator agrees to provide the IRB/EC with all appropriate material, including a copy of 
the Informed Consent Form. The study will not be initiated until the Investigator obtains written 
approval of the research plan and the Informed Consent Form from the appropriate IRB/EC and 
copies of these documents are received by the Sponsor. Appropriate reports on the progress of 
this study will be made by the Investigator to the IRB/EC and Sponsor in accordance with 
applicable government regulations and in agreement with the policies established by the 
Sponsor. The Sponsor ensures that the IRB/EC complies with the requirements set forth in 
21 CFR Part 56.


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17.0 REFERENCE LIST
1.
Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30(2):191-7. Epub 
1987/08/01.
2.
Chrubasik S, Model A, Black A, Pollak S. A randomized double-blind pilot study 
comparing Doloteffin and Vioxx in the treatment of low back pain. Rheumatology (Oxford). 
2003;42(1):141-8. Epub 2003/01/02.
3.
Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic 
neuropathy: a randomized, controlled study. Neurology. 2001;57(3):505-9. Epub 2001/08/15.
4.
Cleeland CS, Nakamura Y, Mendoza TR, Edwards KR, Douglas J, Serlin RC. 
Dimensions of the impact of cancer pain in a four country sample: new information from 
multidimensional scaling. Pain. 1996;67(2-3):267-73. Epub 1996/10/01.
5.
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Annals 
of the Academy of Medicine, Singapore. 1994;23(2):129-38. Epub 1994/03/01.
6.
ECDEU assessment manual for psychopharmacology Rockville, MD: U.S. National 
Institute of Health, Psychopharmacology Research Branch; 1976
(https://archive.org/details/ecdeuassessmentm1933guyw).
7.
Murray A, Hagen NA. Hydromorphone. Journal of pain and symptom management. 
2005;29(5 Suppl):S57-66. Epub 2005/05/24.
8.
Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical 
applications in cancer patients. Supportive care in cancer : official journal of the Multinational 
Association of Supportive Care in Cancer. 2001;9(2):84-96. Epub 2001/04/18.
9.
Tejwani GA, Rattan AK. The role of spinal opioid receptors in antinociceptive effects 
produced by intrathecal administration of hydromorphone and buprenorphine in the rat. 
Anesthesia and analgesia. 2002;94(6):1542-6, table of contents. Epub 2002/05/29.
10.
Plummer JL, Cmielewski PL, Reynolds GD, Gourlay GK, Cherry DA. Influence of 
polarity on dose-response relationships of intrathecal opioids in rats. Pain. 1990;40(3):339-47. 
Epub 1990/03/01.
11.
Allen JW, Horais KA, Tozier NA, Wegner K, Corbeil JA, Mattrey RF, et al. Time course 
and role of morphine dose and concentration in intrathecal granuloma formation in dogs: a 
combined magnetic resonance imaging and histopathology investigation. Anesthesiology. 
2006;105(3):581-9. Epub 2006/08/26.
12.
Guedes AG, Papich MG, Rude EP, Rider MA. Comparison of plasma histamine levels 
after intravenous administration of hydromorphone and morphine in dogs. Journal of veterinary 
pharmacology and therapeutics. 2007;30(6):516-22. Epub 2007/11/10.
13.
Bennett AD, Everhart AW, Hulsebosch CE. Intrathecal administration of an NMDA or a 
non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model 


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of chronic central pain after spinal cord injury. Brain research. 2000;859(1):72-82. Epub 
2000/03/18.
14.
Stearns L, Boortz-Marx R, Du Pen S, Friehs G, Gordon M, Halyard M, et al. Intrathecal 
drug delivery for the management of cancer pain: a multidisciplinary consensus of best clinical 
practices. The journal of supportive oncology. 2005;3(6):399-408. Epub 2005/12/15.
15.
Surgeons British Pain Society. Intrathecal Drug Delivery for the Management of Pain and 
Spasticity in Adults; Recommendations for Best Clinical Practice2008 August 2008
(http://www.britishpainsociety.org/book_ittd_main.pdf).
16.
Lee YS, Park YC, Kim JH, Kim WY, Yoon SZ, Moon MG, et al. Intrathecal 
hydromorphone added to hyperbaric bupivacaine for postoperative pain relief after knee 
arthroscopic surgery: a prospective, randomised, controlled trial. European journal of 
anaesthesiology. 2012;29(1):17-21. Epub 2011/05/13.
17.
Du Pen S, Du Pen A, Hillyer J. Intrathecal hydromorphone for intractable nonmalignant 
pain: a retrospective study. Pain Med. 2006;7(1):10-5. Epub 2006/03/15.
18.
Deer T, Krames ES, Hassenbusch SJ, Burton A, Caraway D, Dupen S, et al. 
Polyanalgesic consensus conference 2007: recommendations for the management of pain by 
intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. 
Neuromodulation : journal of the International Neuromodulation Society. 2007;10(4):300-28. 
Epub 2007/10/01.
19.
Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database Syst Rev. 
2002(1):CD003447. Epub 2002/03/01.
20.
Jones TF, Feler CA, Simmons BP, Melton K, Craig AS, Moore WL, et al. Neurologic 
complications including paralysis after a medication error involving implanted intrathecal 
catheters. The American journal of medicine. 2002;112(1):31-6. Epub 2002/01/29.
21.
Johansen MJ, Satterfield WC, Baze WB, Hildebrand KR, Gradert TL, Hassenbusch SJ. 
Continuous intrathecal infusion of hydromorphone: safety in the sheep model and clinical 
implications. Pain Med. 2004;5(1):14-25. Epub 2004/03/05.
22.
Newsome S, Frawley BK, Argoff CE. Intrathecal analgesia for refractory cancer pain. 
Current pain and headache reports. 2008;12(4):249-56. Epub 2008/07/16.
23.
Bennett G, Serafini M, Burchiel K, Buchser E, Classen A, Deer T, et al. Evidence-based 
review of the literature on intrathecal delivery of pain medication. Journal of pain and symptom 
management. 2000;20(2):S12-36. Epub 2000/09/16.
24.
Bennett G, Deer T, Du Pen S, Rauck R, Yaksh T, Hassenbusch SJ. Future directions in 
the management of pain by intraspinal drug delivery. Journal of pain and symptom management. 
2000;20(2):S44-50. Epub 2000/09/16.
25.
Boswell MV, Trescot AM, Datta S, Schultz DM, Hansen HC, Abdi S, et al. 
Interventional techniques: evidence-based practice guidelines in the management of chronic 
spinal pain. Pain physician. 2007;10(1):7-111. Epub 2007/01/27.
26.
Walker SM, Goudas LC, Cousins MJ, Carr DB. Combination spinal analgesic 
chemotherapy: a systematic review. Anesthesia and analgesia. 2002;95(3):674-715. Epub 
2002/08/29.


Mallinckrodt Pharmaceuticals, Inc
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27.
Burton AW, Rajagopal A, Shah HN, Mendoza T, Cleeland C, Hassenbusch SJ, 3rd, et al. 
Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Med. 
2004;5(3):239-47. Epub 2004/09/16.
28.
Droney J, Riley J. Recent advances in the use of opioids for cancer pain. Journal of pain 
research. 2009;2:135-55. Epub 2009/01/01.
29.
Hassenbusch SJ, Stanton-Hicks M, Covington EC, Walsh JG, Guthrey DS. Long-term 
intraspinal infusions of opioids in the treatment of neuropathic pain. Journal of pain and 
symptom management. 1995;10(7):527-43. Epub 1995/10/01.
30.
Hassenbusch SJ, Portenoy RK, Cousins M, Buchser E, Deer TR, Du Pen SL, et al. 
Polyanalgesic Consensus Conference 2003: an update on the management of pain by intraspinal 
drug delivery-- report of an expert panel. Journal of pain and symptom management. 
2004;27(6):540-63. Epub 2004/05/29.
31.
Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic 
noncancer pain: a systematic review and meta-analysis of efficacy and safety. Journal of pain 
and symptom management. 2008;35(2):214-28. Epub 2008/01/08.
32.
Tobias JD. A review of intrathecal and epidural analgesia after spinal surgery in children.
Anesthesia and analgesia. 2004;98(4):956-65, table of contents. Epub 2004/03/26.
33.
Gradert TL, Baze WB, Satterfield WC, Hildebrand KR, Johansen MJ, Hassenbusch SJ. 
Safety of chronic intrathecal morphine infusion in a sheep model. Anesthesiology. 
2003;99(1):188-98. Epub 2003/06/27.
34.
Peng PW, Fedoroff I, Jacques L, Kumar K. Survey of the practice of spinal cord 
stimulators and intrathecal analgesic delivery implants for management of pain in Canada. Pain 
research & management : the journal of the Canadian Pain Society = journal de la societe 
canadienne pour le traitement de la douleur. 2007;12(4):281-5. Epub 2007/12/15.
35.
Turner JA, Sears JM, Loeser JD. Programmable intrathecal opioid delivery systems for 
chronic noncancer pain: a systematic review of effectiveness and complications. The Clinical 
journal of pain. 2007;23(2):180-95. Epub 2007/01/24.
36.
Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of 
chronic pain with intrathecal clonidine or clonidine/opioid combinations. Journal of pain and 
symptom management. 2003;26(1):668-77. Epub 2003/07/10.
37.
Atli A, Theodore BR, Turk DC, Loeser JD. Intrathecal opioid therapy for chronic 
nonmalignant pain: a retrospective cohort study with 3-year follow-up. Pain Med. 
2010;11(7):1010-6. Epub 2010/05/25.
38.
Deer TR, Kim C, Bowman R, Tolentino D, Stewart C, Tolentino W. Intrathecal 
ziconotide and opioid combination therapy for noncancer pain: an observational study. Pain 
physician. 2009;12(4):E291-6. Epub 2009/08/12.
39.
Anderson VC, Cooke B, Burchiel KJ. Intrathecal hydromorphone for chronic 
nonmalignant pain: a retrospective study. Pain Med. 2001;2(4):287-97. Epub 2004/04/23.
40.
Dominguez E, Sahinler B, Bassam D, Day M, Lou L, Racz G, et al. Predictive value of 
intrathecal narcotic trials for long-term therapy with implantable drug administration systems in 


Mallinckrodt Pharmaceuticals, Inc
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chronic non-cancer pain patients. Pain practice : the official journal of World Institute of Pain. 
2002;2(4):315-25. Epub 2006/12/13.
41.
Doleys DM, Brown JL, Ness T. Multidimensional Outcomes Analysis of Intrathecal, 
Oral Opioid, and Behavioral-Functional Restoration Therapy for Failed Back Surgery Syndrome: 
A Retrospective Study With 4 Years' Follow-up. Neuromodulation : journal of the International 
Neuromodulation Society. 2006;9(4):270-83. Epub 2006/10/01.
42.
Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA. Comparison of histamine release in 
human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology. 
1985;62(2):124-9. Epub 1985/02/01.
43.
Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and hydromorphone 
hydrochloride. Journal of pain and symptom management. 1999;17(1):70-2. Epub 1999/01/27.
44.
Rosow CE, Moss J, Philbin DM, Savarese JJ. Histamine release during morphine and 
fentanyl anesthesia. Anesthesiology. 1982;56(2):93-6. Epub 1982/02/01.
45.
Babul N, Darke AC, Hagen N. Hydromorphone metabolite accumulation in renal failure. 
Journal of pain and symptom management. 1995;10(3):184-6. Epub 1995/04/01.
46.
Kittelberger KP, Buchheit TE, Rice SF. Self-extraction of intrathecal pump opioid. 
Anesthesiology. 2004;101(3):807. Epub 2004/08/27.
47.
Coyne PJ, Hansen LA, Laird J, Buster P, Smith TJ. Massive hydromorphone dose 
delivered subcutaneously instead of intrathecally: guidelines for prevention and management of 
opioid, local anesthetic, and clonidine overdose. Journal of pain and symptom management. 
2004;28(3):273-6. Epub 2004/09/01.
48.
Rosenfeld DM, Trentman T, Patel NP. Pontine hemorrhage following a recently 
implanted intrathecal drug delivery system. Pain practice : the official journal of World Institute 
of Pain. 2009;9(4):312-6. Epub 2009/06/09.
49.
McMillan MR, Doud T, Nugent W. Catheter-associated masses in patients receiving 
intrathecal analgesic therapy. Anesthesia and analgesia. 2003;96(1):186-90, table of contents. 
Epub 2002/12/31.
50.
Coffey RJ, Burchiel K. Inflammatory mass lesions associated with intrathecal drug 
infusion catheters: report and observations on 41 patients. Neurosurgery. 2002;50(1):78-86; 
discussion -7. Epub 2002/02/15.
51.
Ramsey CN, Owen RD, Witt WO, Grider JS. Intrathecal granuloma in a patient receiving 
high dose hydromorphone. Pain physician. 2008;11(3):369-73. Epub 2008/06/05.
52.
Deer T, Krames ES, Hassenbusch S, Burton A, Caraway D, Dupen S, et al. Management 
of Intrathecal Catheter-Tip Inflammatory Masses: An Updated 2007 Consensus Statement From 
An Expert Panel. Neuromodulation : journal of the International Neuromodulation Society. 
2008;11(2):77-91. Epub 2008/04/01.
53.
Deer TR. A prospective analysis of intrathecal granuloma in chronic pain patients: a 
review of the literature and report of a surveillance study. Pain physician. 2004;7(2):225-8. Epub 
2006/07/27.


Mallinckrodt Pharmaceuticals, Inc
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54.
Coffey RJ, Allen JW. Not all intrathecal catheter tip MRI findings are inflammatory 
masses. Anesthesia and analgesia. 2007;104(6):1600-2; author reply 2. Epub 2007/05/22.
55.
Allen JW, Horais KA, Tozier NA, Yaksh TL. Opiate pharmacology of intrathecal 
granulomas. Anesthesiology. 2006;105(3):590-8. Epub 2006/08/26.
56.
The Prevention and Treatment of Missing Data in Clinical Trials. . Committee on 
National Statistics, Division of Behavioral and Social Sciences Education. : The National 
Academies Press. Washington DC, 2010
(http://www.ncbi.nlm.nih.gov/books/NBK32775/pdf/TOC.pdf).
57.
US Food and Drug Administration Safety Alert. Opioid Pain Medicines: Drug Safety 
Communication – New Safety Warnings Added to Prescription Opioid Medications. US Dept of 
Health and Human Services. Posted 22 March 2016. 
http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/uc
m491715.htm


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Appendix A: Schedule of Study Procedures
Table A- 1: Schedule of Study Procedures: Screening and Chronic Dosing Phase to Day 56
Study Procedure
Screening
Baseline
Titration
Visit Schedule (Days 1 to 56)
Study Daya
Dayb -14 to 1
Dayc -3 to 1
Optional Dayse
Day 1
Day 7
Day 14
Day 21
Day 28
Day 42
Day 56
Signed informed consent
X
Medical history
X
Complete physical examination
X
Vital signs, Height and Weight
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test
X
X
ECGf
X
CBC, CMP, urinalysisg
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
X
Hydromorphone HCl (Pump Refill)
Xd
Xd
Pump Dose Adjustment
X
X ----------------------------------------------------------------------------
Oral Opioid (180 mg morphine-eq/day max.) h
X ----------------------------------------------------------------------------
Plasma concentration (PK) of Hydromorphone
X
X
Clinical evaluation for Inflammatory Granulomai
X
X
X
X
X
X
X
X
VASPIj
X
X
X
X
X
X
X
X
X
X
COWSk
X
X
X
SOWSk
X
X
X
SF-MPQk
X
X
X
X
BPIk
X
X
X
X
PGICk
X
X
X
X
a.
Study day is based on Day 1 defined as the first day at a therapeutic dose of intrathecal hydromorphone. There is no Day 0 in this trial. Visit days are ±2 day for Optional Titration Days and Days
1, 7, 14, 21, 28, 42 56 and 77. “Unscheduled Visits” will be considered as “Optional Days” for the purpose of study assessments.
b.
Screening period is 14 days. Baseline, Screening and Initiation of Dosing (ie, Optional Titration Day or Day 1) visits may be combined.
c.
Baseline evaluations must be performed within 72 hours prior to initial dose reduction to wean subject off current opioid therapy. Baseline and Screening visit may be combined.
d.
Pump refills are conducted during regular visits only when necessary based on the pump alarm date, or on Day 1 and Day 77 per protocol regardless of pump alarm date.
e.
For subjects requiring titration to a therapeutic dose of intrathecal hydromorphone, up to five (5) additional study days are allowed for titration (Days A, B, C, D and E) each 3 to 7 days apart.
f.
ECG is to be performed in triplicate for all measurements at Screening and Baseline period.
g.
Blood samples are to be obtained during screening. Includes RBC morphology, reticulocyte count, and standard urinalysis.
h.
Oral supplemental opioid medications are allowed up to 180 mg-morphine equivalence per day up to Day 77. As the intrathecal dose of hydromorphone is optimized oral supplement should be 
reduced as much as possible.
i.
If there are clinical signs of an inflammatory granuloma as defined in Section 3.3, the Medical Monitor should be notified and an MRI or CT myelogram scheduled to confirm the pathology of the 
granuloma.


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j.
VASPI will be obtained in the clinic using a standardized scale.
k.
COWS, SOWS, BPI, SF-MPQ and PGIC will be conducted at each office visit as specified in the Schedule of Events. Assessments conducted per the Schedule of Events should be completed prior 
to any dose adjustment or providing any oral supplemental opioid medication for withdrawal symptoms or rescue, if possible.


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Table A- 2: Schedule of Study Procedures: Final 7 Days of Continuous Dosing, Randomized Withdrawal and Efficacy Evaluation Period
Study Procedure
Visit Scheduleb
Days 77 to 119
Study Daya
Day 77
Day 84
Day 91
Day 98
Day 105
Day 112
Day119e
Final Visitf
Complete physical examination
X
X
X
Vital signs and Weight
X
X
X
X
X
X
X
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
Hydromorphone HCl (Pump Refill)
X
Hydromorphone Titration c, d
X
X
X
X
X
Hydromophone HCl (removal from pump)
X
Oral Opioid (60 mg morphine-eq/day max.) g
X ----------------------------------------------------------------------------
Plasma concentration (PK) of Hydromorphone
X
X
Clinical evaluation for Inflammatory 
Granulomas h
X
X
X
X
X
X
X
X
VASPI Assessmenti
X ---------------------------------------------------------------------------------------------------
COWS Assessmentj
X
X
X
X
X
X
SOWS Assessmentj
X
X
X
X
X
X
Short-Form McGillj
X
X
X
X
BPIj
X
X
X
X
PGICj
X
X
X
X
a.
Study day is based on Day 1 defined as the first day at a therapeutic dose of intrathecal hydromorphone., There is no Day 0 in this trial.
b.
All visit days are +/- 1 day after Day 77 except for the final study visit.
c.
On Days 84, 91, 98, 105 and 112 all subjects will have a pump adjustment. For those subjects randomized to maintain therapy, the adjustments will be a mock change to the dose, but no change 
will actually be made. For control group subjects randomized to be weaned off medication, the pump will be adjusted to give a 75%, 50%, 25%, 12.5% and 0% dose on each successive dose 
adjustment visit.
d.
For the 0% dose, the pump will be set to the shipping mode (minimal speed possible)
e.
On Day 119, or after treatment failure, all subject will receive scheduled Day 119 assessments before rescue medication is administered, if possible. If the subject cannot come to the site prior to 
rescue, they will be instructed to take a final VASPI using the remote monitoring device prior to taking oral rescue medication. After completion of the randomization period or rescue due to 
intolerable pain, or if dropped prior to randomization, subjects may be eligible to enter the CNS-HYD202US long term safety trial for an additional 12-months of hydromorphone therapy.
f.
Subjects that discontinue or do not enter the CNS-HYD202US trial will return to the site 2 weeks after their last visit to have a final study visit This visit can be +/- 4 days of the target date.
g.
Oral opioid up to a maximum of 60 mg morphine-equivalence of oral opioid per day is allowed after Day 84 only for the purpose of managing withdrawal symptoms experienced as subject’s are 
weaned off intrathecal medication. Doses of opioids in excess of 60 mg morphine-equivalence oral opioid per day, or other interventions to manage pain will be considered a treatment failure.
h.
If there are clinical signs of an inflammatory granuloma as defined in Section 3.3, the Medical Monitor should be notified and an MRI or CT myelogram scheduled to confirm the pathology of the 
granuloma.
i.
VASPI assessments are performed twice daily by the subject using a remote monitoring device that can capture VASPI measurements at approximately the same times each day.
j.
COWS, SOWS, BPI, SF-MPQ and PGIC will be conducted at each office visit as specified in the Schedule of Events. Assessments conducted per the Schedule of events should be completed prior 
to any dose adjustment or providing any oral supplemental opioid medication for withdrawal symptoms or rescue, if possible.


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Appendix B: National Cancer Institute
Common Terminology Criteria for Adverse Events
Version 4.03
Publication Date: 14 June 2010
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


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Appendix C: Visual Analog Scale of Pain Intensity (VASPI)


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Appendix D: Clinical Opiate Withdrawal Scale (COWS)


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Appendix E: Subjective Opiate Withdrawal Scale (SOWS)


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Appendix F: Brief Pain Inventory (BPI)


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Appendix G: Patient Global Impression of Change (PGIC)


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Appendix H: Short-Form McGill Pain Questionnaire 
(SF-MPQ)



SAP_001.pdf: 
Protocol CNS-HYD201US  
 
Piramal Critical Care, Ltd. 
04 Feb 2019 
Page 1 of 38 
Version 5.0 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Title: 
A Controlled, Two-Arm, Parallel Group, Randomized Withdrawal 
Study To Assess The Safety And Efficacy Of Hydromorphone 
Hydrochloride Delivered By Intrathecal Administration Using A 
Programmable Implantable Pump 
Protocol: 
CNS-HYD201US 
Sponsor: 
Piramal Critical Care, Ltd. 
Suite 4, Ground 4, Heathrow Boulevard 
East Wing, 280 Bath Road 
West Drayton, England, UB7 0DQ 
Date: 
04 February 2019, Version 5.0 
 
Status: 
 
Final 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 Protocol CNS-HYD201US 
 
Piramal Critical Care, Ltd. 
04 Feb 2019 
Page 3 of 38 
Version 5.0 
 
 
 
 
Table of Contents 
GLOSSARY OF TERMS..................................................................................................................... 4 
1 
Introduction ................................................................................................................................ 5 
2 
Purpose of the Analyses ............................................................................................................. 5 
3 
Study Objectives ........................................................................................................................ 6 
4 
Study Design .............................................................................................................................. 6 
5 
Data Management .................................................................................................................... 13 
6 
Definition of Populations ......................................................................................................... 13 
7 
Definition of Study Endpoints ................................................................................................. 14 
7.1 Primary Efficacy Endpoint ...................................................................................................... 14 
7.2 Secondary Endpoints ............................................................................................................... 15 
7.3 Pharmacokinetic Outcomes...................................................................................................... 17 
8 
Statistical Methods ................................................................................................................... 17 
8.1 Sample Size .............................................................................................................................. 18 
8.2 Randomization and Masking ................................................................................................... 18 
8.3 Subject Discontinuation and Replacement of Subjects ........................................................... 19 
8.4 Final Analyses and Reporting .................................................................................................. 19 
8.5 Handling of Missing Data ........................................................................................................ 19 
8.6 Comments on Statistical Analysis ........................................................................................... 20 
9 
Statistical Analyses .................................................................................................................. 21 
9.1 Subject Disposition .................................................................................................................. 21 
9.2 Screening and Baseline Characteristics ................................................................................... 21 
9.3 Study Drug Exposure and Compliance .................................................................................... 23 
9.4 Protocol Violations .................................................................................................................. 23 
9.5 Efficacy Analyses .................................................................................................................... 23 
9.6 Safety Analyses ........................................................................................................................ 24 
9.7 Clinical and Subjective Opiate Withdrawal Scales .................................................................. 27 
10 
Summary of Amendments to the SAP ..................................................................................... 28 
Appendix A ........................................................................................................................................ 31 
Appendix B ........................................................................................................................................ 35 


 Protocol CNS-HYD201US 
 
Piramal Critical Care, Ltd. 
04 Feb 2019 
Page 4 of 38 
Version 5.0 
 
GLOSSARY OF TERMS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory 
BSA 
Body Surface Area 
CMH 
Cochran-Mantel-Haenszel 
COWS 
Clinical Opiate Withdrawal Scale 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
HEENT 
Head, eyes, ears, nose, and throat 
ITT 
Intent-to-Teat 
IWRS 
Interactive Web-based Randomization System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent-to-treat 
PK 
Pharmacokinetics 
PGIC 
Patient Global Impression of Change 
PTM 
Personal Therapy Manager 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-MPQ 
Short-Form McGill Pain Questionnaire 
SOC 
System Organ Class 
SOWS 
Subjective Opiate Withdrawal Scale 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
VASPI 
Visual Analog Scale of Pain Intensity 
WHO-DD 
World Health Organization Drug Dictionary 


 Protocol CNS-HYD201US 
 
Piramal Critical Care, Ltd. 
04 Feb 2019 
Page 5 of 38 
Version 5.0 
1 Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be 
performed for the analysis of data from Protocol CNS-HYD201US, “A Controlled, Two-
Arm, Parallel Group, Randomized Withdrawal Study To Assess The Safety And Efficacy Of 
Hydromorphone Hydrochloride Delivered By Intrathecal Administration Using A 
Programmable Implantable Pump.” 
 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): Guidance on 
Statistical Principles in Clinical Trials. 
 
This SAP is an amended version of the original SAP written for the CNS-HYD201US 
protocol that was finalized on 25 September 2012 as Version 1.1 and as amended as: 
1. Version 2.0 on 15 November 2012, 
2. Version 2.1 on 20 December 2012 
3. Version 2.2 on 30 July 2013 
4. Version 2.3 on 11 March 2014 
5. Version 3.0 on 18 December 2014, 
6. Version 4.0 on 24 June 2016, and 
7. Version 5.0 on 01 August 2016 
 
The following documents were reviewed in preparation of this SAP: 
 
 Final Clinical Protocol CNS-HYD201US, Version 5.0, issued 01 August 2016 
 
 Current case report forms for Protocol CNS-HYD201US 
 
2 Purpose of the Analyses 
The purpose of this SAP is to outline the planned analyses to be completed to support the 
Clinical Study Report (CSR) for Protocol CNS-HYD201US. The planned analyses identified 
in this SAP will be included in regulatory submissions and/or future manuscripts. Also, 
exploratory analyses not necessarily identified in this SAP may be performed to support the 
clinical development program.  Any post-hoc or unplanned analyses not identified in this 
SAP will be clearly identified in the CSR. 
Additionally, the purpose of this Amended SAP is to clarify the analyses to be performed as 
well as the timing of various analyses.  During the course of the trial, the Sponsor changed 
from Mallinckrodt Pharmaceuticals, Inc. (MNK) to Piramal Critical Care, Ltd. (Piramal).  
As occurs with such changes, the priorities for the study differed from original plans.  
Piramal made a business decision to proceed with only the safety portion of the study.  All 
subjects completed the study as planned and all data modules pertaining to the safety 
analysis were cleaned and queried.   Efficacy data modules were cleaned and queried up to 


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11 September 2017, when the decision was made to analyze safety data only.  Database lock 
occurred on 18 October 2017.  Subsequently, Piramal made the decision to go forward with 
the entire analysis of the study.  As the study was already unblinded, no further cleaning of 
the efficacy data modules was permitted.  The efficacy analyses will be completed on the 
locked database, with no changes to the data, unless obvious date errors (i.e., incorrect year 
resulting in a record incompatible with the study timeline).   This Amended SAP describes 
the updates in conduct and analysis of the trial due to these changes. 
 
3 Study Objectives 
The purpose of this clinical study is to demonstrate the efficacy and safety of a 2mg/mL and 
10mg/mL formulation of hydromorphone hydrochloride dosed by the intrathecal route of 
administration in subjects with chronic pain that require continuous opioid treatment through 
an implantable micro-infusion pump. 
 
Primary Objective 
 
The primary objective of this clinical trial is to demonstrate the superiority of intrathecal 
hydromorphone hydrochloride in subjects who are on an optimal dose compared with those 
who have their dose titrated downward during the randomized withdrawal period as 
measured by treatment failure rate. 
 
 
Secondary Objective 
 
To evaluate the safety of hydromorphone hydrochloride given by the intrathecal route of 
administration. 
 
4 Study Design 
This is a controlled, prospective, randomized withdrawal trial to be conducted at 10 to 30 US 
clinical trial sites that are experienced with the use of intrathecal opioids.  All subjects will be 
entered after signing an IRB approved informed consent.  Subjects who currently have a 
SynchroMed® II Implantable Infusion Pump will be eligible to enroll in this trial.  For 
subjects that do not have a current infusion pump implanted, they may be consented and 
enrolled only after pump implantation and stabilization on intrathecal morphine. Subjects 
who are naïve to intrathecal therapy, may be enrolled 2-weeks after pump implantation with 
a SynchroMed® II Implantable Infusion Pump. Subjects entering the study should have a 
reasonable likelihood of benefiting from intrathecal treatment with an opioid such as 
hydromorphone hydrochloride. 
 
Subjects entering the trial on a stable dose of intrathecal hydromorphone hydrochloride may 
be converted directly to study medication without dose adjustment. Subjects who will be 


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converted from their current intrathecal morphine therapy to intrathecal hydromorphone 
hydrochloride according to the following scheme: 
 
Subject Status on Morphine 
Conversion 
Ratio 
Dose ≤ 30 mg IT morphine and tolerating therapy well 
1 : 6 1 
Dose > 30 mg IT morphine or subject has significant side effects 
on morphine 
1 : 12 2 
1Conversion is based on mg-morphine equivalence such that for each 6 mg morphine sulfate the dose is 
converted to 1 mg hydromorphone hydrochloride. 
2Conversion is based on mg-morphine equivalence such that for each 12 mg morphine sulfate the dose is 
converted to 1 mg hydromorphone hydrochloride. 
 
 
The conversion will take place by removing the current product in the pump and then 
replacing the contents with hydromorphone hydrochloride for intrathecal injection. At the 
discretion of the investigator the pump reservoir may be rinsed with preservative free sterile 
saline or the study medication (hydromorphone hydrochloride for intrathecal injection). The 
subject should be contacted by telephone 24 hours after initiating study medication.  If 
combinations were used in the previous intrathecal therapy, oral medications permitted by the 
protocol may be provided to replace the intrathecal combination regimen. However, for the 
duration of the CNS-HYD201US trial only hydromorphone hydrochloride may be used in the 
intrathecal pump as monotherapy. 
 
Depending on the subjects starting dose on hydromorphone hydrochloride, either a 2 mg/mL 
or 10 mg/mL formulation of hydromorphone hydrochloride for intrathecal injection may be 
used. 
 
Dosing with the SynchroMed II Implantable Infusion pump may utilize simple continuous, 
complex continuous with or without Personal Therapy Manager (PTM) dosing. 
 
Subjects who are converted directly to a therapeutic dose of hydromorphone hydrochloride 
(i.e. direct conversion from previous treatment with hydromorphone, or a 1:6 conversion 
from a therapeutic dose of morphine) will start the study on Day 1. For subjects that are 
converted to a lower dose based on the 1:12 conversion scheme for safety reasons, up to five 
(5) optional study visits (Days A, B, C, D and E) are permitted to allow dose titration to a 
therapeutic dose that is well tolerated. These optional visit days may be from three (3) to 
seven (7) days apart. After the subject achieves a therapeutic dose of hydromorphone 
hydrochloride the procedures starting with Day 1 of the study will be followed to ensure the 
subject is treated for the full 12 week period at a therapeutic dose of intrathecal 
hydromorphone hydrochloride. 
 
Dose adjustments thereafter will be allowed by adjusting the pump speed, with a maximum 
dose adjustment of no more than 50% if the current dose is 0.5 mg or less, and 25% for 


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subjects on doses above 0.5 mg, as described in the following scheme: 
 
 
 
Dose of Hydromorphone 
Hydrochloride IT 
Maximum Dose 
Adjustment 
0.1 to 0.5 mg 
50 % 
> 0.5 mg 
25 % 
 
 
A maximum dose of 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any 
time during this study. For PTM dosing this maximum dose includes the subject activated 
doses that are allowed by the device programming. 
 
Subjects may be given oral supplemental medication for pain up to a maximum of 180 mg- 
equivalent morphine per day prior to Day 77 of treatment, however, the objective of the trial 
during this period is to achieve an optimal dose of intrathecal hydromorphone hydrochloride 
and reduce or eliminate any oral supplement.  Oral supplement in excess of 180 mg-
equivalent morphine per day or other interventions due to intolerable pain, is not permitted 
and the subject will be withdrawn from the trial and weaned off intrathecal hydromorphone 
hydrochloride and converted to other appropriate pain therapies. From Day 77 to Day 119 
or day of rescue, subjects are permitted up to 60 mg-equivalent morphine per day only to 
manage possible withdrawal symptoms. 
 
On Day 77 the pump should be refilled with intrathecal hydromorphone and any final 
adjustments made to the daily dose or programming. On Day 77, the subject will be given a 
remote monitoring device to measure VASPI scores twice daily in the morning (5:30 am to 
12:00 noon) and in the evening (6:00 pm to 11:45 pm). After Day 77 and during the 
randomized double-blind period there should be no dose adjustments to intrathecal 
hydromorphone hydrochloride other than those dictated by the protocol for subjects on the 
control arm who have their dose titrated downward.  After Day 77, there should also be no 
changes to the pump programming for simple continuous, complex continuous or PTM 
dosing regimens until after the completion of the trial. 
 
At the end of the 12 week continuous dosing period, subjects who meet criteria for 
randomization will be randomized in a 1:1 ratio to either remain at their current dose of 
hydromorphone or who have their dose titrated downward (control group) in a blinded 
fashion. The criteria for randomization is defined as an average VASPI score of 50 mm or 
less on a scale of 100 mm for the last 5 days with daily pain measurements prior to 
randomization on Day 84. After Day 77 the subject should be weaned off any oral 
supplement of opioid or other prescription medications prior to randomization.  For those 
subjects randomized to be withdrawn from hydromorphone therapy on Day 84, the pump 
speed will be adjusted to decrease the total daily dose each 7 days (± 1 day), starting at a dose 


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of 75%, 50%, 25%, 12.5% and approximately 0% of the dose at the time of randomization. 
For PTM dosing, the base continuous dose and the PTM dose would be decreased by the 
specified percentages above. The total maximum dose of 10 mg/day will be the combined 
total of the decreased base continuous dose and PTM dose. For those subjects randomized to 
stay on their current dose of hydromorphone hydrochloride, they will also return to the clinic 
on the same schedule for assessments and for mock pump adjustments.  The blind will be 
maintained by having an independent unblinded medical professional at the site to manage 
the pump infusion rate and medication provided to the subject. 
 
Pain assessments using the VASPI scale will continue twice daily (morning and evening) 
from Day 77 prior to the randomization period and throughout the randomized withdrawal 
period. COWS and SOWS assessments will be performed at specified time points to assess 
any withdrawal symptoms.  Subjects will be permitted a maximum of 60 mg of morphine-
equivalent oral opioid per day during the randomized withdrawal period only for the purpose 
of managing withdrawal symptoms.  This oral supplement is not intended to manage pain and 
should be provided only if the subject starts to experience withdrawal symptoms.  No other 
changes to prescription medications or non-pharmacologic interventions being used for pain 
are allowed from Days 84 to 119, or treatment failure. 
 
Baseline pain for the double-blind randomized withdraw period is defined as the average of 
the last 5 days of the last 7 days with daily pain measurements while on the optimal 
intrathecal dose of hydromorphone hydrochloride, between Days 77 to 83 of the open-label 
dosing period. 
 
 
After randomization, a treatment failure will be defined by the following criteria: 
 
1. A subject who experiences an increase of 20 mm or more above the baseline value 
on a 100 mm VASPI based on the average of 5 days, or 
2. A subject who experiences intolerable pain that in the opinion of the investigator 
requires intervention (i.e. rescue), or 
3. A subject who has other interventions for pain that violate the protocol from Day 84 
to 119 that includes: 
a. Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent to 
manage withdrawal symptoms, or 
b. Has a change in oral prescription pain medications or non-pharmacologic 
treatments being administered to manage pain. 
 
Note: A subject who does not have sufficient data for evaluation, drops out for any 
other reasons that are not listed above or who experiences withdrawal syndrome as 
identified by COWS > 12 during the double-blind treatment phase will not be 
classified as a treatment failure in the primary efficacy analysis. 
 
Prior to rescue medication being administered, subjects will complete Day 119 study 
assessments, if possible.  After confirming with the investigator that it is acceptable to take 


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rescue medication, if a subject cannot return to the study site for assessments they will be 
instructed to complete a VASPI score on the remote monitoring device immediately prior to 
taking oral rescue medication.  If the subject can return to the site, rescue may be performed 
by either oral medication being administered or by increasing the pump speed to achieve a 
therapeutic dose of hydromorphone hydrochloride, or both. 
 
Subjects will be evaluated for side effects and clinical complications associated with the use 
of intrathecal hydromorphone hydrochloride. Signs and symptoms of an inflammatory 
granuloma, including radicular pain, loss of drug efficacy, and spinal cord compression will 
be monitored by clinical assessments.  If there are clinical signs or symptoms identified 
which may indicate an inflammatory mass formation, an MRI with or without contrast or CT 
myelogram will be performed to evaluate the potential presence of an inflammatory 
granuloma as opposed to other catheter related problems that may result in reduced delivery 
or clinical symptoms. Events that may be related to an inflammatory granuloma will be 
classified as a confirmed granuloma, suspected granuloma, other catheter related problem 
(confirmed not caused by a granuloma) or other clinical event caused by the underlying 
disease or other non-catheter/product related event. 
 
Following the 5 week randomized withdrawal period, all randomized subjects may be 
allowed to continue on intrathecal hydromorphone hydrochloride for up to 12 months of 
safety evaluation by entering the open-label safety study (CNS-HYD202US). Subjects in the 
control group who had their dose titrated down will be first titrated back onto intrathecal 
hydromorphone hydrochloride as part of the CNS-HYD202US protocol.  Subjects who do 
not experience adequate benefit or cannot tolerate intrathecal hydromorphone hydrochloride 
during the 12-week chronic dosing period will not enter the randomized withdrawal period 
of the trial, and thus not be eligible for the long term treatment protocol.  Subjects who 
experience a drug related adverse event that requires discontinuation after randomization will 
also not be qualified for the long- term extension study, CNS-HYD202US. Subjects will be 
followed for safety for the duration of their treatment with intrathecal hydromorphone 
hydrochloride using the SynchroMed® II Programmable Pump or until the study completion. 
Table 1 and Table 2 contain the study schedule of assessments. 


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Table 1:  Schedule of Study Procedures: Screening and Chronic Dosing Phase to Day 56 
 
Study Procedure 
Screening 
Baseline 
Titration 
Visit Schedule (Days 1 to 56) 
Study Daya 
Dayb -14 to 1 
Dayc -3 to 1 
Optional Dayse 
Day 1 
Day 7 
Day 14 
Day 21 
Day 28 
Day 42 
Day 56 
Signed informed consent 
X 
Medical history 
X 
Compete physical exam 
X 
Vital signs, Height and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
ECGf 
X 
CBC, CMP, urinalysisg 
X 
Concomitant medication assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hydromorphone  HCl (Pump Refill) 
Xd 
Xd 
Pump Dose Adjustment 
X 
X ----------------------------------------------------------------------------
Oral Opioid (180 mg morphine-eq/day max.) h 
X ----------------------------------------------------------------------------
Plasma concentration (PK) of Hydromorphone 
X 
X 
Clinical evaluation for Inflammatory Granulomai 
X 
X 
X 
X 
X 
X 
X 
X 
VASPIj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COWSk 
X 
X 
X 
SOWSk 
X 
X 
X 
SF-MPQk 
X 
X 
X 
X 
BPIk 
X 
X 
X 
X 
PGICk 
X 
X 
X 
X 
a. 
Study day is based on Day 1 defined as the first day at a therapeutic dose of intrathecal hydromorphone.  There is no Day 0 in this trial.  Visit days are ±2 day for Optional Titration Days and Days 
1, 7, 14, 21, 28, 42 56 and 77.  “Unscheduled Visits” will be considered as “Optional Days” for the purpose of study assessments. 
b. 
Screening period is 14 days. Baseline, Screening and Initiation of Dosing (i.e. Optional Titration Day or Day 1) visits may be combined. 
c. 
Baseline evaluations must be performed within 72 hours prior to initial dose reduction to wean subject off current opioid therapy.  Baseline and Screening visit may be combined. 
d. 
Pump refills are conducted during regular visits only when necessary based on the pump alarm date, or on Day 1 and Day 77 per protocol regardless of pump alarm date. 
e. 
For subjects requiring titration to a therapeutic dose of intrathecal hydromorphone, up to five (5) additional study days are allowed for titration (Days A, B, C, D and E) each 3 to 7 days apart. 
f. 
ECG is to be performed in triplicate for all measurements at Screening and Baseline period. 
g. 
Blood samples are to be obtained during screening.  Includes RBC morphology, reticulocyte count, and standard urinalysis. 
h. 
Oral supplemental opioid medications are allowed up to 180 mg-morphine equivalence per day up to Day 77. As the intrathecal dose of hydromorphone is optimized oral supplement should be 
reduced as much as possible. 
i. 
If there are clinical signs of an inflammatory granuloma as defined in Section 3.3 (of the protocol), the Medical Monitor should be notified and an MRI or CT myelogram scheduled to confirm the 
pathology of the granuloma. 
j. 
VASPI will be obtained in the clinic using a standardized scale. 
k. 
COWS, SOWS, BPI, SF-MPQ and PGIC will be conducted at each office visit as specified in the Schedule of Events.  Assessments conducted per the Schedule of Events should be completed 
prior to any dose adjustment or providing any oral supplemental opioid medication for withdrawal symptoms or rescue, if possible. 


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Table 2:  Schedule of Study Procedures: Final 7 Days of Continuous Dosing, Randomized Withdrawal and Efficacy Evaluation Period 
 
Study Procedure 
Visit Scheduleb 
Days 77 to 119 
Study Daya 
Day 77 
Day 84 
Day 91 
Day 98 
Day 105 
Day 112 
Day 119e 
Final Visitf 
Compete physical exam 
X 
X 
X 
Vital signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Hydromorphone  HCl (Pump Refill) 
X 
Hydromorphone Titration c, d 
X 
X 
X 
X 
X 
Hydromophone HCl (removal from pump) 
X 
Oral Opioid (60 mg morphine-eq/day max.) g 
X ----------------------------------------------------------------------------
Plasma concentration (PK) of Hydromorphone 
X 
X 
Clinical evaluation for Inflammatory 
Granulomas h 
X 
X 
X 
X 
X 
X 
X 
X 
VASPI Assessmenti 
X ---------------------------------------------------------------------------------------------------
COWS Assessmentj 
X 
X 
X 
X 
X 
X 
SOWS Assessmentj 
X 
X 
X 
X 
X 
X 
Short-Form McGillj 
X 
X 
X 
X 
BPIj 
X 
X 
X 
X 
PGICj 
X 
X 
X 
X 
a. 
Study day is based on Day 1 defined as the first day at a therapeutic dose of intrathecal hydromorphone.,  There is no Day 0 in this trial. 
b. 
All visit days are +/- 1 day after Day 77 except for the final study visit. 
c. 
On Days 84, 91, 98, 105 and 112 all subjects will have a pump adjustment. For those subjects randomized to maintain therapy, the adjustments will be a mock change to the dose, but no change 
will actually be made.  For control group subjects randomized to be weaned off medication, the pump will be adjusted to give a 75%, 50%, 25%, 12.5% and 0% dose on each successive dose 
adjustment visit. 
d. 
For the 0% dose, the pump will be set to the shipping mode (minimal speed possible) 
e. 
On Day 119, or after treatment failure, all subject will receive scheduled Day 119 assessments before rescue medication is administered, if possible.  If the subject cannot come to the site prior to 
rescue, they will be instructed to take a final VASPI using the remote monitoring device prior to taking oral rescue medication. After completion of the randomization period or rescue due to 
intolerable pain, subjects may be eligible to enter the CNS-HYD202US long term safety trial for an additional 12-months of hydromorphone therapy. 
f. 
Subjects that discontinue or do not enter the CNS-HYD202US trial will return to the site 2 weeks after their last visit to have a final study visit. This visit can be +/- 4 days of the target date. 
g. 
Oral opioid up to a maximum of 60 mg morphine-equivalence of oral opioid per day is allowed after Day 84 only for the purpose of managing withdrawal symptoms experienced as subjects are 
weaned off intrathecal medication. Doses of opioids in excess of 60 mg morphine-equivalence oral opioid per day, or other interventions to manage pain will be considered a treatment failure. 
h. 
If there are clinical signs of an inflammatory granuloma as defined in Section3.3 (of the protocol), the Medical Monitor should be notified and an MRI or CT myelogram scheduled to confirm the 
pathology of the granuloma. 
i. 
VASPI assessments are performed twice daily by the subject using a remote monitoring device that can capture VASPI measurements at approximately the same times each day. 
j. 
COWS, SOWS, BPI, SF-MPQ and PGIC will be conducted at each office visit as specified in the Schedule of Events.  Assessments conducted per the Schedule of events should be completed prior 
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5 Data Management 
Data management, including database design, development of the data dictionary, and coding 
of adverse events and medications will be performed at Social and Scientific Services (S-3), 
the CRO managing data base entry and cleaning. Data will be entered into electronic case 
report forms (eCRFs) at the study sites.  Logic and consistency checks will be performed on 
all data entered into the eCRFs to ensure accuracy and completeness. Refer to the Data 
Management Plan for further details.  An ePRO device will also be used to collect VASPI 
measurements from Day 77 to 119. 
 
A paper CRF page will be used by the Unblinded Pump Operator to record dose 
administration information during Days 84 to 119. The protocol indicates that this CRF page 
will be held at the site and collected after the subject has completed the trial for manual entry 
into the database. The actual practice being followed is that the unblinded site representative 
sends this CRF page to the unblinded Clinical Research Associate for monitoring. These 
CRFs will be collected at the end of the study and sent in for manual entry into the database. 
 
6 Definition of Populations 
The intent-to-treat (ITT) population includes all subjects who are randomized on Day 84 to 
either the active or control group in the Double-Blind Randomized Withdrawal portion of 
this study and receive at least one day of hydromorphone hydrochloride intrathecal treatment 
during the randomization period.  All efficacy analyses will be carried out using the ITT 
population.  In all efficacy analyses, subjects will be included in the group based on the 
group to which they were randomized. 
 
The Safety population includes all subjects who have study medication loaded into their 
intrathecal pump (i.e. any exposure to study medication). Safety analyses will be carried out 
using the Safety population.  In all safety analyses, subjects will be included in the group 
based on the treatment they received (i.e., randomized withdrawal or same dose 
hydromorphone continuation).  Subjects who do not reach the point of randomization will be 
included in the overall column only. 
 
Inclusion in the ITT and Safety populations will be determined programmatically from the 
CRF data. 
 
Exclusion of Subjects from Site 028 
During the execution of the study, it came to the attention of the Sponsor and SSS that the 
integrity of the data from Site 028 (Dr. Minkowitz, Advanced Invasive Pain Management, 
Houston, TX) may have been compromised due to documentation shortcomings, errors and 
oversights on the part of the investigator. After careful review of the data integrity and 
regulatory implications of this situation, the Sponsor made the decision to terminate the 
Investigator from the study and to close the study site for enrollment.   No Case Report Form 
reported data queries would be generated from that point forward.  However, it was 


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determined that all data from this site would be included in the analyses of safety, but should 
not be included in the analysis of efficacy.   
 
Since this decision was taken mid-way through the study, efficacy analyses will be performed 
on two populations, excluding or including subjects from Site 028.  The primary efficacy 
analysis will be performed on the population:  ITT/Randomized Subjects Excluding Site 
028.  Additionally, selected analyses will be performed on the population All ITT/ 
Randomized Subjects as a sensitivity analysis. Documentation of the site closure can be 
found in Appendix B. 
 
7 
Definition of Study Endpoints 
 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects who are treatment failures during 
the double-blind randomized withdrawal period.  After randomization, a treatment failure 
will be defined by the following criteria: 
1. Any subject who experiences an increase of 20 mm or more above the baseline value 
on a 100 mm VASPI based on the average of 5 days, or 
2. Any subject who experiences intolerable pain that in the opinion of the 
investigator requires intervention (i.e. rescue), or 
3. Any subject who has other interventions for pain that violate the protocol from Day 84 
to 119 that includes: 
a. Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent 
to manage withdrawal symptoms, or 
b. Has a change in non-opioid oral prescription medications or non-
pharmacological treatments being administered for the management of pain. 
 
Note: A subject who does not have sufficient data for evaluation, drops out for any other 
reasons that are not listed above or who experiences withdrawal syndrome as identified by 
COWS > 12 during the double-blind treatment phase will not be classified as a treatment 
failure in the primary efficacy analysis. 
 
VASPI Calculation Algorithm 
 
VASPI scores will routinely be collected twice each day. The daily VASPI score from Day 77 
to 119 will be computed as follows: 
 
 
As the average of the two scores when both of the twice-daily VASPI measures are 
present. 
 
 If only one score is present, then the daily score will be equal to that non-missing value. 
 


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 If both scores are missing, then the daily score will be missing. 
 
The 5-day baseline (Days 77-83) average VASPI will be computed as follows: 
 
 If the daily score is present on days 79, 80, 81, 82, and 83, then the 5-day average is 
the average of days 79-83. 
 
 If one of the daily scores from days 79-83 is missing, then the day 78 value (if 
present) will be included in the 5 daily scores to be averaged.  If the day 78 value is 
also missing, then the day 77 value will instead be used. 
 
 If two of the daily scores from days 79-83 are missing, then the day 78 and day 77 
values (if present) will be included in the 5 daily scores to be averaged. 
 
During the double-blind randomized withdrawal period, the 5-day average will be calculated 
as follows: 
 If the daily score is present on all 5 consecutive days, then the 5-day average will be 
calculated using the data from these days. 
 
 If any of the daily scores are missing, then the 5-day average will be based on the 
most recent 5 days for which daily scores are available. 
 
 If 5 post-randomization daily scores are not available, then the average of the 
subject’s available scores will be used. 
 
In the event that a subject rescues for intolerable pain a self-initiated VASPI will be obtained, 
if possible.  In this event, it is possible that more than one VASPI score may be obtained in 
the AM or PM time periods.  In the event of more than one VASPI score recorded in the AM 
(12:01 am to 12:00 noon) or in the PM (12:01 noon to 12:00), the AM or PM values will be 
averaged to obtain a single AM or PM score for pain that will then be used in the algorithm 
above. 
 
7.2 
Secondary Endpoints  
Secondary endpoints include: 
 
 The most important secondary endpoint is safety of intrathecal hydromorphone as 
assessed through collection of adverse events (AEs) and serious adverse events (SAEs) 
during the conduct of the trial. Particular attention will be paid to: 
o Rate of confirmed granulomas that are verified by MRI, CT Myelogram or 
by surgery. 
o Rate of possible granulomas 
 
Other secondary endpoints include: 
 


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 Short-Form McGill Pain Questionnaire (SF-MPQ) 
 Time to Rescue after Randomization 
 Oral Opioid Supplement Consumption 
 Brief Pain Inventory (BPI) 
 Patient Global Impression of Change (PGIC) 
 
7.2.1 Short-form McGill Pain Questionnaire (SF-MPQ) 
 
The SF-MPQ consists of a 15 item pain rating index. The severity of each item will be scored 
as None (0), Mild (1), Moderate (2), or Severe (3).  The total SF-MPQ score is the sum of the 
severity scores for each item. The total score can range from 0 to 45. During the double-blind 
treatment period, the SF-MPQ will be collected on Days 84, 98, 112, and 119. 
 
 
7.2.2 Time to Rescue after Randomization  
 
If at any time a subject experiences intolerable pain, the subject will be allowed to rescue. 
The day, time and amount of rescue medication provided to address the intolerable pain 
will be recorded.  Rescue may include providing oral or intravenous medication, as well as 
increasing the pump speed to titrate the subject back to an effective dose of intrathecal 
hydromorphone. 
 
The number of days to rescue will be calculated by calculating the number of hours between 
the time of randomization and the time of rescue. The number of hours will then be divided 
by 24 to obtain the number of days. 
 
 
7.2.3 Oral Opioid Supplement Consumption 
 
The total number of milligrams consumed of any oral opioid product from Day 84 through the 
end of study will be calculated for each subject.  Opioid consumption was to be recorded via 
subject diaries throughout the study.  As a rule, subject diaries are not queried for data 
clarification purposes.  Occasionally, a subject would report opioid consumption that was not 
recorded on the subject diary.  This data was then recorded on the concomitant medication 
CRF page by the study site staff.  In order to calculate the total opioid consumption during 
the randomized phase of the trial, both CRF modules will be utilized.  Medications recorded 
as concomitant medications, with ATC3 text equal to “OPIOIDS” and with a start date on or 
after the randomization date will be combined with records from the Opioid Products 
Administered CRF.   
 
7.2.4 Brief Pain Inventory (BPI) 
 


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The BPI will consist of two domains, pain severity and pain interference with functioning. 
 
Pain severity will be evaluated by rating pain on a scale from 0 (no pain) to 10 (pain as bad as 
you can imagine) for the ‘worst’, ‘least’, and ‘average’ pain experienced in the past 24 hours, 
as well as, the pain experienced ‘now’.  In addition, a calculated mean pain severity score 
will be based on the sum of all 4 of the pain scores divided by 4.  If any of the 4 questions 
are missing, then the calculated mean pain severity score will be considered missing. 
 
Pain interference with daily functioning will be evaluated by rating interference on a scale 
from 0 (does not interfere) to 10 (completely interferes) for ‘general activity’, ‘mood’, 
‘walking ability’, ‘normal work’, ‘relation with other people’, ‘sleep’, and ‘enjoyment of 
life’. A calculated mean pain interference will be based on the sum of non-missing 
interference questions answered divided by the number of questions answered. The mean 
should be set to missing if fewer than 4 pain interference questions are answered. 
 
During the double-blind treatment period, the BPI will be collected on Days 84, 98, 112, 
and 119. 
 
 
7.2.5 Patient Global Impression of Change (PGIC) 
 
The PGIC rating represents observed changes (if any) from the subject’s Baseline Visit in 
activity limitations, symptoms, emotions, and overall quality of life, related to the subject’s 
painful condition.  Change is rated on a 7-point Likert-type scale from 1 (no change) through 7 
(a great deal better).  During the double-blind treatment period, the PGIC will be collected on 
Days 84, 98, 112, and 119. 
 
7.3 
 Pharmacokinetic Outcomes 
Blood samples for determination of the steady state plasma pharmacokinetics (PK) of 
hydromorphone following continuous infusion will be collected during the study. 
 
The total volume of blood drawn for PK analysis is 24 mL as four samples over the course of 
the study. Each PK sample will be a 6 mL of blood collected into a standard plasma sample 
tube and centrifuged to obtain at least 3 mL of plasma.  The sample will be separated into 
two approximately 1.5 mL aliquots and frozen to < -20°C until shipment to the central 
testing facility. 
 
Blood will be collected for analysis of hydromorphone concentration in plasma prior to 
dosing with any daily oral medications (i.e. other oral opioids permitted in the protocol) on 
Day 14, Day 56, 77 and Day 84. 
 
 
8 
Statistical Methods 


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8.1 
Sample Size 
Approximately 150 subjects will be enrolled at up to thirty (30) US investigative sites to 
obtain approximately 80 subjects who qualify for randomization into the double-blind period 
on Day 84.  This enrollment is based on a combined drop out and treatment failure (i.e. > 50 
mm on a 0 to 100 mm VASPI score for the last 5 days with non-missing data prior to the 
double-blind period) rate of approximately 45%. 
 
During the double-blind period, the true treatment failure rate in the hydromorphone 
hydrochloride arm is assumed to be at most 20%. Based on a two-sided, two-sample 
comparison of proportions at the alpha=0.05 level of significance, a sample size of 80 
subjects (40 per arm) will provide greater than 90% power to detect an increase in the 
treatment failure rate of 35% (i.e., the control group who will have their dose titrated 
downward has a failure rate of 55%). 
 
8.2 
Randomization and Masking 
Each subject who is entered into the trial will be assigned an enrollment number by the site, 
that consists of the two digit site number (##) and a subject number consisting of three-digits 
(XXX) by the interactive web based randomization system.  This number will be used for the 
entire duration of the trial. 
 
For subjects who meet the criteria for randomization, a treatment group randomization code 
will be assigned to that subject via an interactive web-based randomization system (IWRS).  
The subject will then be randomized to either remain on the current dose of intrathecal 
hydromorphone or be titrated off therapy starting on Day 84 with a 1:1 ratio. The unblinded 
pump technician at the site will have access to the patient treatment assignment through 
accessing a separate page of the EDC on line.  The unblinded pump technician will have a 
unique user name and password to allow them to access the treatment assignment. 
 
This is a double-blind, randomized study.  After randomization on Day 84, subjects will 
receive either intrathecal hydromorphone hydrochloride or will have their dose titrated 
downward over a 4 week period followed by 1 week at the lowest pump setting. An 
unblinded technician or nurse at the site will be assigned (i.e. Pump Operator) to adjust pump 
speeds during the 5 week double- blind period. The unblinded pump operator will not be 
involved in any other evaluations of the subject and will be instructed to avoid revealing any 
information to study personnel about the group assignment of the subject.  Dosing after 
randomization will be done by randomization code for each subject. Subjects who utilize a 
PTM device will be blinded to the display screen of the PTM. The display screen will be 
covered with a non-transparent tamper resistant tape that will be checked at each visit. The 
PTM device will be able to operate normally, but the screen or any data from the PTM will 
not be visible to the subject. 
 


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8.3 
Subject Discontinuation and Replacement of Subjects 
Subjects may withdraw from the study at any time. Subjects may be discontinued from study 
treatment or the study at the request of the Investigator or Sponsor. Subjects who drop out of 
the study after randomization will not be replaced. 
 
8.4 
Final Analyses and Reporting 
In addition, no database may be locked, randomization code unblinded, or final analyses 
completed until this SAP has been approved.  The final analyses outlined in the protocol and 
in this SAP will be carried out after: 
 The SAP has been approved; 
 The study database has been authorized by the sponsor clinical team as complete 
and final; 
 All analysis populations are determined; and 
 Protocol violations have been identified. 
 
Further exploratory analyses not necessarily identified in this SAP may be performed to 
support the clinical development program. Any post-hoc or unplanned analyses performed 
and not identified in this SAP will be clearly identified in the CSR. 
 
8.5 
Handling of Missing Data 
Unless otherwise noted, missing data will not be imputed. 
 
A subject who does not provide data sufficient to evaluate his/her treatment failure status 
during the double-blind period will not be considered to be a treatment failure.   This 
includes subjects who drop out of the study during this period for any reason other than 
treatment failure. This methodology is aligned with the National Research Council (2010, 
page 24) report on missing data, the estimand is the difference in outcome improvement in 
tolerators.  Because the primary endpoint is defined as a failure rate, and because any subject 
who cannot be defined as a “failure” is a treatment ”success”, the use of this endpoint in a 
randomized withdrawal study minimizes missing data (National Research Council, 2010, 
pages 33-34). 
 
For all secondary efficacy endpoints (other than the time to rescue after randomization and 
oral opioid supplement consumption), last observation carried forward imputation (LOCF) 
will be used for missing data when performing an analysis at Day 119 or the last study visit. 
 
Partially Answered Questionnaires: 
 
When calculating the total score for the SF-MPQ, the Clinical Opiate Withdrawal Scale 
(COWS), and the Subjective Opiate Withdrawal Scale (SOWS), the 20% imputation rule will 
be used for partially answered questionnaires.  If more than 20% of the items for the total 


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score are missing, then the total score will be set to missing.  If 20% or less of the items for 
the total score are missing, then the total score will be calculated as: 
(total of items present) (maximum possible total of items present) 
 (maximum possible total of all items). 
 
For the BPI, follow the rules for missing information discussed in the BPI section. Since the 
PGIC is a single question questionnaire, no imputation will be used. 
 
8.6 
Comments on Statistical Analysis 
 
The following general comments apply to all statistical analyses and data presentations: 
 
Summaries will include frequency and percentages for categorical data and frequency, mean, 
standard deviation, median, minimum, and maximum for quantitative data.  
 Where appropriate and unless otherwise specified, analyses will be presented 
by randomized treatment arm: hydromorphone arm or titrated down (control) 
arm. 
 
 Duration variables will be calculated using the general formula:  Duration = (end 
date – start date) + 1. 
 
 Individual subject listings of all data represented on the eCRFs will be provided to 
facilitate the investigation of tabulated values and to allow for the clinical review of 
all data. 
 
 Version 9.1 or greater of SAS statistical software package will be used to provide 
all summaries, listings, and graphs described in this document. 
 
 All raw data will be presented to the original number of data places. The means and 
medians will be presented to one more decimal place than the raw data. The standard 
deviations will be presented to two more decimal places than the raw data.  For 
averages of averages, the means and medians will also be presented to one more 
decimal place than the raw data and the standard deviations will also be presented to 
two more decimals places than the raw data. 
 
 Generally, the denominator for percentages will be based on the number of subjects 
in the study population. However, for cases where appropriate, the denominator for 
percentages will be based on the number of subjects with non-missing data 
appropriate for summary purposes.  Unless otherwise noted, all percentages will be 
presented to one decimal place. 
 
 There are approximately 10-30 study sites in this study. Due to the large number of 
study sites and the small numbers of subjects per site, the analysis of efficacy 
endpoints will not include adjustments for study site.  However, descriptive 
summaries of the primary endpoint will be provided by site. 


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 Analyses for the randomization phase, Day 84 through Day 119, will be calculated 
for the period defined as randomization date through end of study date, as study day 
of randomization and Day 119 visit  may not always occur on the scheduled study 
days (84 and 119) due to various circumstances. 
 
9 
Statistical Analyses 
9.1 
Subject Disposition 
 
The number and percent of subjects in each of the analysis populations (i.e., ITT, Safety) will 
be summarized by treatment arm and overall.  The number and percent of subjects who 
enrolled in the study, completed the study, who withdrew from the study and their reasons for 
withdrawal will be tabulated by treatment arm and overall.  Subject disposition will be 
summarized using all enrolled subjects.  Enrolled subjects are those subjects who signed the 
informed consent form and receive intrathecal hydromorphone supplied by MNK as GMP 
product for this study.  
A listing summarizing whether subjects completed or discontinued from the study will also be 
presented and the primary reason for discontinuation will be provided for those subjects who 
withdrew. 
 
9.2 
Screening and Baseline Characteristics 
 
 
9.2.1 Demographics and Baseline Characteristics 
 
Descriptive statistics will be used to summarize demographic and baseline characteristics by 
treatment arm and for both treatment arms combined. Subject demographics include sex, age, 
ethnicity, race, height, weight, and body mass index (BMI). Age (in years) will be calculated 
from the date of birth to the date of informed consent. Age will be reported as an integer. BMI 
will be calculated using the following formula: BMI (kg/m2) = weight (kg)/(height (m))2. 
 
All demographic and baseline characteristics will also be listed. 
 
9.2.2 Medical History 
 
Medical history information will be collected at the Screening visit. 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA); the dictionary version will be noted in the CSR. Medical history will be 
summarized by system organ class, preferred term, and treatment arm. Medical history 
verbatim terms and coded terms will be listed. 
 
Listings will also be provided with the following information: 


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 History of intractable pain 
 Implantation of intrathecal pump and prior opioid use prior to pump implantation 
 Surgical intervention(s) for treatment of intractable pain 
 
 
9.2.2 Medications 
 
Prior medications are defined as medications that were taken within 30 days prior to initial 
dosing with study drug.  Concomitant medications are defined as medications taken any time 
after the start of dosing until the final visit.  Medications are also considered concomitant if 
their stop date is unknown or marked as continuing.  Medications will with missing start 
dates will be considered ongoing on the first day of study drug administration except where 
positive confirmation is available that the medication was stopped before study drug 
administration. 
 
The World Health Organization Drug Dictionary (WHO-DD) will be used to classify prior 
and concomitant medications by therapeutic class and preferred term.  The WHO-DD 
version will be noted in the CSR. The number and percentage of subjects receiving 
concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
level 3, preferred term, and treatment arm.  Subjects will be counted only once for an ATC 
class and preferred term, even if the subject took the same medication on multiple occasions.  
Prior medications will be summarized in a similar manner. 
 
A listing of medications will be prepared. 
 
 
9.2.1 12-Lead Electrocardiogram (ECG) 
 
A safety ECG will be performed at screening to assess any cardiovascular abnormalities for the 
purpose of determining eligibility for this trial. The number and percentage of subjects with 
normal, abnormal not clinically significant and abnormal clinically significant ECGs at 
Screening and Baseline will be summarized. 
 
ECG results will also be listed. 
 
 
9.2.2 Laboratory Assessments 
Blood for chemistry, hematology, and urinalysis laboratory tests will be collected at Screening. 
The results will be used to determine the subject’s eligibility for the study.  If abnormal, the 
investigator will describe the abnormality in the eCRF.  Individual laboratory results will not 
be entered into the eCRF.  Abnormal laboratory results (i.e. investigator description of 
abnormalities) will be listed. 
 


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Urine pregnancy tests will also be conducted at Screening and/or Baseline for women of 
childbearing potential.   Pregnancy test results will be listed. 
 
 
9.3 
Study Drug Exposure and Compliance 
A listing containing the date and time the current product was removed from the pump, drug 
concentration, lot number, volume refilled, whether dose adjustments were made, date and 
time of dose changes, the original and changed daily doses, and whether there were any 
problems with the pump refill will be listed. 
 
A dosing summary by treatment arm will be presented for the ITT and Safety populations. 
 
 
9.4 
Protocol Violations 
Violations of the protocol will be recorded appropriately.  Examples might include, but not 
necessarily limited to, the following categories: 
 Inclusion/exclusion criteria violation 
 Prohibited medication use 
 Incorrect treatment or dose 
 Treatment non-compliance 
 Procedure non-compliance 
 Safety observation 
 
Classification of violations from the protocol as minor or major will be decided on a case-by- 
case basis without knowledge of the treatment assigned and before database lock. A listing 
of major protocol violations that impact the evaluation of efficacy will be provided. 
 
9.5 
Efficacy Analyses 
All efficacy endpoints identified in Section 7.1 will be summarized using descriptive statistics 
by treatment arm (and by visit for secondary efficacy endpoints, where applicable).   All 
summaries of efficacy data will be carried out in the ITT population.  All efficacy endpoints 
will also be listed. 
 
9.5.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of subjects who are treatment failures during 
the double-blind randomized withdrawal period.  After randomization, a treatment failure 
will be defined by the following criteria: 
 
1. Any subject who experiences an increase of 20 mm or more above the baseline value 
on a 100 mm VASPI based on the average of 5 days, or 


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2. Any subject who experiences intolerable pain that in the opinion of the 
investigator requires intervention (i.e. rescue), or 
3. Any subject who has other interventions for pain that violate the protocol from Day 84 
to 119 that includes: 
a. Requires oral opioid supplement in excess of 60 mg/day morphine-equivalent 
to manage withdrawal symptoms, or 
b. Has a change in non-opioid oral prescription medications or non-
pharmacological treatments being administered for the management of pain. 
 
Note: A subject who does not have sufficient data for evaluation, drops out for any other 
reasons that are not listed above or who experiences withdrawal syndrome as identified by 
COWS > 12 during the double-blind treatment phase will not be classified as a treatment 
failure in the primary efficacy analysis. 
 
The number and percentage of subjects with treatment failure during the double-blind period 
will be summarized by treatment group. Differences in treatment group failure rates will be 
test using a Pearson’s chi-square (two-sided) test at the 5% level of significance. The 
corresponding 95% confidence interval for failure rate will be provided. 
 
9.5.2 Secondary Efficacy Analyses 
Safety is the most important secondary endpoint.  Other secondary endpoints include quality 
of life / pain scale assessments. 
 
For the purpose of efficacy analyses, ‘baseline’ will be Day 84. 
 
The change from baseline) to Day 119 in the BPI (pain severity ‘worst’, pain severity 
‘average’, calculated mean pain severity, and calculated mean pain interference with 
function.) will be analyzed using an ANCOVA model with treatment group as a factor and 
the baseline BPI as a covariate.  The change from baseline to Day 119 in the SF-MPQ and in 
oral opioid supplement consumption will also be analyzed using this same type of ANCOVA 
model. 
 
The distributions of time to rescue will be summarized in each treatment group using the 
Kaplan- Meier method. Subjects who do not receive rescue medication will be censored at 
their date of last follow-up.  The two groups will be compared using the log rank test. 
 
The PGIC on Day 119 (or at the time of rescue) will be analyzed using the Cochran-Mantel- 
Haenszel mean score test (using equally spaced scores). 
 
All secondary analyses will be carried out using two-sided tests at the 5% level of 
significance. 
 
9.6 
Safety Analyses 
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summary tables and subject data listings. Safety will primarily be addressed through 
examination of the incidence and severity of adverse events, as well as, the rate of possible 
granulomas and the rate of confirmed granulomas. Other safety assessments include vital 
signs. 
 
9.6.1 Adverse Events  
Unless otherwise noted, analyses will be based on treatment-emergent adverse events 
(TEAEs), defined as those events that begin or worsen in severity after the first treatment 
with study drug at Baseline.  For AEs with missing start dates, the AE will be considered 
treatment-emergent unless there is additional information indicating that the AE started prior 
to the first study drug treatment. 
 
Adverse events will be coded to system organ class and preferred term using MedDRA; the 
dictionary version will be noted in the CSR. AE severity will be assessed and summarized 
using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. 
 
AE incidence tables will include the number and percentage of subject reporting at least one 
AE, as well as, the number and percentage of AEs summarized by MedDRA system organ 
class and preferred term. Subjects with two or more AEs in the same system organ class will 
be counted once for that system organ class; likewise for preferred term. For ‘by severity’ 
and ‘by relationship to study treatment’ tables, subjects will be counted once at the maximum 
severity and at the strongest causal relationship, respectively.  Summaries of treatment-
related AEs will include those events classified by the investigator as having a possible or 
probable relationship to study drug (or unknown relationship).  Tables will be produced for 
the following: TEAEs, treatment-related TEAEs, TEAEs by strongest relationship, TEAEs 
by maximum severity, treatment-emergent serious adverse events (TESAEs), TESAEs by 
strongest relationship, treatment-related SAEs, and TESAEs by maximum severity.  An 
overall AE summary table will provide top level subject counts for all the AE analyses noted.  
In addition, the AE summary table will include the number and percentage of subjects 
reporting any AE (including non TEAEs), the number and percentage of subjects with an AE 
that led to withdraw of study drug, and the number and percentage of subjects with an AE 
with outcome of death. 
 
Complete listings of all AEs will be provided (non TEAEs will be flagged with a ‘*’).  In 
addition, data listings of all SAEs, AEs leading to discontinuation, and AEs leading to death 
will also be provided. 
 
 
9.6.2 Vital Signs and Weight 
Systolic and diastolic blood pressure (mmHg), radial pulse (beats/minute), breathing rate 
(breaths/minute), and temperature (°C) will be obtained at Baseline and each study visit. 
Weight (kg) will be collected at screening and each study visit. 


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All vital signs and weight measurements as well as change from Baseline for these 
measurements will be summarized by treatment arm at each visit.  A listing of weight and 
vital signs will also be provided. 
 
The number and percentage of subjects with potentially clinically significant vital signs will 
be summarized at each visit by vital sign and treatment arm. A listing of subjects with 
potentially clinically significant vital signs will also be presented. Table 3 contains the 
criteria for identifying potentially clinically significant vital sign values. 
 
    
Table 3:  Criteria for Identifying Potentially Clinically Significant Vital Sign Values 
 
 
Vital Sign Parameter 
Criteria 
Systolic Blood Pressure (mmHg) 
>160 mmHg or increase of ≥20 mmHg from baseline 
Systolic Blood Pressure (mmHg) 
<95 mmHg or decrease of ≥20 mmHg from baseline 
Diastolic Blood Pressure (mmHg) 
>110 mmHg or increase of ≥15 mmHg from baseline 
Diastolic Blood Pressure (mmHg) 
<50 mmHg or decrease of ≥15 mmHg from baseline 
Heart Rate (bpm*) 
>100 bpm or increase of ≥15 bpm from baseline 
Heart Rate (bpm*) 
<50 bpm or decrease of ≥15 bpm from baseline 
Weight (kg) Gain 
>10% weight increase 
Weight (kg) Loss 
>10% weight decrease 
*bpm = Beats per minute 
 
9.6.3 Physical Examinations 
 
A complete physical examination will be conducted at Screening, Day 84, Day 119, and at the 
Final Visit.  The number and percentage of normal and abnormal physical examinations will be 
summarized by body system and treatment arm at each visit.  Any clinically significant 
physical examination findings will be reported as AEs or SAEs. Physical examination 
findings will also be listed for each visit. 
 
 
9.6.4 Granulomas 
A clinical evaluation for mass formation will be conducted at baseline, Days 1, 7, 14, 21, 28, 
42, 56, 77, 84, 91, 98, 105, 112, 119, and the Final Visit. However, at any time that clinical 
signs and symptoms warrant, an evaluation for the potential for a granuloma will be 
conducted. 
 
Signs and symptoms of an inflammatory granuloma, including radicular pain, sudden loss of 
drug efficacy that is not attributed to other assignable causes, and spinal cord compression at 
the level of the catheter tip will be monitored. If there are signs or symptoms identified 
which may indicate an inflammatory mass formation, an MRI (with and without contrast) or 


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CT scan will be performed (with consent of the subject) to evaluate the potential presence of 
an inflammatory granuloma as opposed to other catheter related problems that may result in 
reduced delivery or clinical symptoms. 
 
All data captured with regard to possible or confirmed inflammatory granulomas will be 
listed, including the date of clinical evaluation for an inflammatory mass, signs and/or 
symptoms of the granuloma, and all MRI or CT scan results. The incidence and rate of 
possible granuloma, as well as, the incidence and rate of confirmed granuloma will be 
summarized by treatment group. 
 
The method of inflammatory granuloma assessment will be summarized by the number and 
percentage of subjects in the following categories: 
 Subjects with clinical signs and symptoms of a granuloma 
 Subjects with clinical signs and symptoms of granuloma, but MRI/CT not performed 
 Subjects with clinical signs and symptoms of granuloma, MRI/CT performed 
 Subjects with confirmed granuloma by MRI/CT via independent radiologist or surgery 
 
All signs and symptoms data related to mass formation including MRI or CT information will 
be listed. 
 
9.6.5 Subgroup Analysis 
 
A supportive exploratory subgroup analysis by site will be done for the primary endpoint of 
treatment failure. Due to the potential for having sites with very small enrollment numbers, 
only descriptive statistics will be presented. 
 
 
9.7 
Clinical and Subjective Opiate Withdrawal Scales 
The COWS assessment will assess the severity of 11 opiate withdrawal symptoms. Each 
symptom severity score ranges from 0 (asymptomatic) to a maximum of 3, 4, or 5 (severe 
based on criteria for the individual symptom). A total score is calculated based on the sum of 
the individual symptoms scores. 
 
The SOWS assessment will assess the severity of 18 subjective symptoms associated with 
opiate withdrawal. Each symptom severity score ranges from 0 (Not at All) to 4 (Extreme). 
A total score is calculated based on the sum of the individual symptoms scores. 
 
During the double-blind treatment period, the COWS and SOWS assessments will be 
performed at Days 84, 91, 98, 105, 112, and 119 to assess any withdrawal symptoms. The 
COWs and SOWs total scores will be summarized at each visit and the changes from baseline 
(i.e. Day 84) to each visit will also be summarized by treatment arm.  Individual item scores 
and the total score for the COWS and SOWS will also be listed. 
 
 


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10 
Summary of Amendments to the SAP 
After the initial SAP approval (version 1.0), all major or minor amendments will be 
summarized in the table below. 
 
Version 
Change (Reason) 
2.0 
 Section 4 text regarding catheter line aspiration deleted (to be 
consistent with protocol text amendment as version 2.2 dated 02Jul 
2013). 
 Text in sections 4, 7.1, and 9.7.1 regarding treatment failure criteria 
updated to further clarify interventions meeting failure criteria and to 
clarify that subjects who discontinue prematurely after randomization 
without sufficient info to evaluate failure will be deemed a failure (to 
be consistent with protocol text which was amended). 
 Reference to interim analysis deleted in section 8.4 (no interim analysis 
planned). 
 Section 9.8 moved to be section 9.6.5 (improve flow). 
3.0 
 Ownership reference to CNS changed to be MNK (updated to 
acknowledge MNKs acquirement of the intrathecal hydromorphone 
product from CNS). 
 Objectives and general study design updates to be consistent with 
protocol amendment 2.3 dated 11March2014). 
 Text in sections 4, 7.1, and 9.7.1 regarding treatment failure criteria 
updated to further clarify that subjects with a COW>12 cannot be counted 
as a failure and subjects who discontinue prematurely after randomization 
without sufficient info to evaluate failure will be deemed a non-failure 
instead of failure (to be consistent with protocol text which was amended, 
note this was partly due to FDA feedback regarding failure definition and 
their particular concerns with true failure being undistinguishable from 
opiate withdrawal). 
 Sample size changed from 150 randomized to 80 randomized and power 
calculations updated (to match amended protocol, note the initial sample 
size estimates were likely based on underestimated predicted treatment 
differences in failure rates. Internal decision for adjustment was made 
based on group and executive approval. Enrollment was vas limited at 
the time of adjustment and no study data were used for assessments.) 
 Section 9.5.2 COWS > 12 sensitivity analyses dropped (not applicable 
given that the failure definition was updated to exclude subjects with 
COWS > 12 as failures). 


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4.0 
 Typos corrected and clarification text added throughout document 
(cleanup of document) 
 Updated study information in sections 1 to 4 and section 7.2 (very minor 
updates to match exact language within the protocol) 
 Section 5 updated regarding process used for the dose CRF on Days 84 
to 119 (clarified that the unblinded site representative sends this CRF 
page to the unblinded CRA for monitoring rather than this CRF 
remaining on site until the subject completes the study, note: this 
actual process does not impact blinding). 
 Updated throughout ‘Time to Rescue after Randomized Withdraw’ to be 
‘Time to Rescue after Randomization’ (improved terminology but no 
change in intent) and updated start time of randomization (time of 
randomization on Day 84 more appropriate than dose time on Day 84). 
 Updated analyses of BPI (analysis was updated to conventional 
published description whereby the BPI is assessed based on 2 
domains separately: pain severity and interference with daily 
function). 
 Deleted section 7.2.6 (unnecessary repeat of safety endpoints). 
 In section 8.3, deleted text regarding subjects re-entering the study (this 
text does not belong in the SAP) and clarified that subjects who drop out 
after randomization are not replaced (clarified because subjects 
dropping out prior to randomization are replaced). 
 Updated section 8.5 to clarify missing data rules for secondary 
endpoints (updated to indicate missing data rule is different for BPI 
vs other secondary endpoint measures). 
 BSA calculations dropped from section 9.2.1 (not applicable in this 
setting per Medical Monitor). 
 Updated medical history text to describe coding of terms (clarification). 
 Removed analyses of ECG and laboratory data (ECG and lab measures 
are not collected however text added that abnormality text recorded on 
the CRF by the investigator will be listed). 
 Changed protocol deviation to protocol violation (to match MNK standards). 
 In section 9.5, ‘by center’ primary efficacy exploratory analyses 
moved to subgroups section 9.6.5 and dropped for secondary 
endpoints (sample size previously reduced to 80 randomized subjects 
so ‘by center’ not as meaningful for all efficacy endpoints). 
 Added analyses text for primary endpoint to section 9.5.1 
(methodology comparing active vs titrated treatment arms described in 
sample size section but not in current section). 


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 In section 9.5.2, ‘baseline’ clarified as randomization/Day 84 for 
efficacy (clarification added but intent was always to use 
randomization day as baseline for efficacy) and dropped repeated 
measures analyses (sample size previously reduced to 80 subjects and 
likely hood for intermittent missing questionnaires make analysis less 
meaningful). 
 Adverse events text (section 9.6.1), Vitals text (section 9.6.2), and 
Granuloma text (section 9.6.4) updated (to improve flow and match 
language within the companion safety study HYD202). 
 Subgroup analyses by PTM vs continuous and pump/catheter replacement 
vs non- replacement dropped and exploratory ‘by study site’ exploratory 
analyses of primary efficacy endpoint moved to this section from another 
section (sample size previously reduced to 80 randomized subjects so 
subgroup analyses anticipated to be too small to be meaningful). 
 In section 9.7 additional text added regarding COWS and SOWS 
(informational addition only) and ‘baseline’ clarified as 
randomization/Day 84 (clarification added but intent was always to use 
randomization day as baseline for efficacy). 
 Added Summary of Amendments section to the SAP (provide historical 
reference) 
 
5.0 
 Described the timeline of safety and efficacy analyses 
 Added ITT, Excluding Subjects from Site 028 Population 
 Added Appendix A – list of Tables, Listings and Figures for output 
 Added Appendix B -  documentation of Site 028 closure 
 Clarified calculations of opioid consumption. 
 Clarified the randomization period as the time from date of randomization 
through end of study, rather than Day 84 through Day 119. 
 
 
 
 


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Appendix A 
 
The following Tables, Listings and Figures are anticipated to be produced to display the results 
of the statistical analyses.  Additions or deletions to this list may be made in order to produce 
the analyses described in this SAP.  
 
 Number 
Title 
Analysis 
Population 
Tables 
 
14.1.1 
Subject Disposition 
All Enrolled Subjects 
14.1.2 
Analysis Populations 
All Enrolled Subjects 
14.1.3 
Demographics and Baseline Characteristics 
All Enrolled Subjects 
14.1.4 
Medical History 
All Enrolled Subjects 
14.1.5.1 
Prior Medications 
All Enrolled Subjects 
14.1.5.2 
Concomitant Medications 
All Enrolled Subjects 
14.1.6 
12-Lead Electrocardiogram 
All Enrolled Subjects 
14.2.1.1.1 
Treatment Failure Rate  
ITT 
14.2.1.1.2 
Treatment Failure Rate  
ITT Excluding Site 028 
14.2.1.2 
Treatment Failure Rate by Site 
ITT 
14.2.2.1 
Time to Rescue after Randomization 
ITT 
14.2.2.2 
Time to Rescue after Randomization 
ITT Excluding Site 028 
14.2.3.1.1 
Pain Indicators Summary 
ITT 
14.2.3.1.2 
Pain Indicators Summary 
ITT Excluding Site 028 
14.2.3.1.3 
Oral Opioid Supplement Consumption 
ITT 
14.2.3.1.4 
Oral Opioid Supplement Consumption 
ITT Excluding Site 028 
14.2.3.1.5 
Patient Global Impression of Change Summary 
ITT 
14.2.3.1.6 
Patient Global Impression of Change Summary 
ITT Excluding Site 028 
14.2.3.2.1 
Brief Pain Inventory - Pain Severity Measures 
ITT 
14.2.3.2.2 
Brief Pain Inventory - Pain Severity Measures 
ITT Excluding Site 028 
14.2.3.3.1 
Brief Pain Inventory  - Pain Interference 
ITT 
14.2.3.3.2 
Brief Pain Inventory  - Pain Interference 
ITT Excluding Site 028 
14.2.3.4.1 
Patient Global Impression of Change (PGIC) 
ITT 
14.2.3.4.2 
Patient Global Impression of Change (PGIC) 
ITT Excluding Site 028 
14.2.3.5.1 
Short-form McGill Pain Questionnaire (SF-MPQ) 
ITT 
14.2.3.5.2 
Short-form McGill Pain Questionnaire (SF-MPQ) 
ITT Excluding Site 028 
14.2.3.6.1 
Visual Analog Scale of Pain Intensity (VASPI) 
ITT 
14.2.3.6.2 
Visual Analog Scale of Pain Intensity (VASPI) 
ITT Excluding Site 028 
14.3.1.1.1 
Overview of Adverse Events - Open Label Phase 
Safety 
14.3.1.1.2 
Overview of Adverse Events - Randomized Phase 
Safety 


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14.3.1.1.3 
Overview of Adverse Events - Overall 
Safety 
14.3.1.2.1 
Incidence of Adverse Events by System Organ Class 
and Preferred Term - Open Label Phase 
Safety 
14.3.1.2.2 
Incidence of Adverse Events by System Organ Class 
and Preferred Term - Randomized Phase 
Safety 
14.3.1.2.3 
Incidence of Adverse Events by System Organ Class 
and Preferred Term - Overall 
Safety 
14.3.1.3.1 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term - Open Label Phase 
Safety 
14.3.1.3.2 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term - Randomized Phase 
Safety 
14.3.1.3.3 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term - Overall 
Safety 
14.3.1.4.1 
Incidence of Adverse Events by System Organ Class, 
Preferred Term and Severity to Study Drug - Open 
Label Phase 
Safety 
14.3.1.4.2 
Incidence of Adverse Events by System Organ Class,  
Preferred Term and Severity to Study Drug - 
Randomized Phase 
Safety 
14.3.1.4.3 
Incidence of Adverse Events by System Organ Class , 
Preferred Term and Severity to Study Drug - Overall 
Safety 
14.3.1.5.1 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term and Severity to 
Study Drug - Open Label Phase 
Safety 
14.3.1.5.2 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term and Severity to 
Study Drug- Randomized Phase 
Safety 
14.3.1.5.3 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term and  Severity to 
Study Drug - Overall 
Safety 
14.3.1.6.1 
Incidence of Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug -
Open Label Phase 
Safety 
14.3.1.6.2 
Incidence of Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug -
Randomized Phase 
Safety 
14.3.1.6.3 
Incidence of Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug -
Overall 
Safety 
14.3.1.7.1 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term, and Relationship to 
Study Drug - Open Label Phase 
Safety 
14.3.1.7.2 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term, and Relationship to 
Study Drug - Randomized Phase 
Safety 


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14.3.1.7.3 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term, and Relationship to 
Study Drug - Overall 
Safety 
14.3.5.1.1 
Vital Signs  - Open Label Phase 
Safety 
14.3.5.1.2 
Vital Signs  - Randomized Phase 
ITT 
14.3.5.2.1 
Potentially Clinically Significant Vital Signs - Open 
Label Phase 
Safety 
14.3.5.2.2 
Potentially Clinically Significant Vital Signs -  
Randomized Phase 
ITT 
14.3.5.3.1 
Physical Examination Findings by Body System - 
Open Label Phase 
Safety 
14.3.5.3.2 
Physical Examination Findings by Body System - 
Randomized Phase 
ITT 
14.3.5.4 
Granuloma Assessment 
All Enrolled Subjects 
14.3.6.1 
Study Drug Exposure Summary - Open Label Phase 
Safety  
14.3.6.2 
Study Drug Exposure Summary - Randomized Phase 
Safety 
14.3.6.3 
Study Drug Exposure  Summary - Overall 
Safety 
14.4.1.1 
Clinical Opiate Withdrawal Scale (COWS) 
Assessment 
ITT 
14.4.1.2 
Clinical Opiate Withdrawal Scale (COWS) 
Assessment 
ITT Excluding Site 028 
14.4.2.1 
Subjective Opiate Withdrawal Scale (SOWS) 
Assessment 
ITT 
14.4.2.2 
Subjective Opiate Withdrawal Scale (SOWS) 
Assessment 
ITT Excluding Site 028 
Figures 
14.2.2.1 
Kaplan-Meier Curve for Time to Rescue 
ITT 
14.2.2.2 
Kaplan-Meier Curve for Time to Rescue 
ITT Excluding Site 028 
Listings 
16.2.1 
Subject Disposition 
All Enrolled Subjects 
16.2.2 
Subject Demographics  
All Enrolled Subjects 
16.2.3.1 
Medical History 
All Enrolled Subjects 
16.2.3.2 
History of Intractable Pain 
All Enrolled Subjects 
16.2.3.3 
Implantation of Intrathecal Pump 
All Enrolled Subjects 
16.2.3.4 
Surgical Intervention for Intractable Pain 
All Enrolled Subjects 
16.2.4 
Prior and Concomitant Medication 
All Enrolled Subjects 
16.2.5.1 
12-Lead ECG 
All Enrolled Subjects 
16.2.5.2 
Laboratory Summary 
All Enrolled Subjects 
16.2.5.3 
Laboratory Results - Pregnancy 
All Enrolled Subjects 
16.2.6 
Protocol Deviations 
All Enrolled Subjects 
16.2.7.1 
Intolerable Pain Assessment - Rescue 
All Enrolled Subjects 
16.2.7.2 
Visual Analog Scale of Pain Intensity (VASPI) 
All Enrolled Subjects 


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16.2.7.3 
Brief Pain Inventory (BPI) 
All Enrolled Subjects 
16.2.7.4 
Patients' Global Impression of Change (PGIC) 
All Enrolled Subjects 
16.2.7.5 
Short-Form McGill Pain Questionnaire (SF-MPQ) 
All Enrolled Subjects 
16.2.8.1 
Adverse Events 
All Enrolled Subjects 
16.2.8.2 
Serious Adverse Events 
All Enrolled Subjects 
16.2.8.3 
Adverse Events Leading to Discontinuation 
All Enrolled Subjects 
16.2.8.4 
Adverse Events Leading to Death 
All Enrolled Subjects 
16.2.9 
Non-Pharmaceutical Intervention 
All Enrolled Subjects 
16.2.10 
Oral Opioid Supplements 
All Enrolled Subjects 
16.2.11 
Vital Signs 
All Enrolled Subjects 
16.2.12 
Physical Examination Assessments 
All Enrolled Subjects 
16.2.13.1 
Clinical Evaluation of Inflammatory Mass Formation 
All Enrolled Subjects 
16.2.13.2 
Signs or Symptoms of Granuloma 
All Enrolled Subjects 
16.2.13.3 
MRI and CT Myelogram 
All Enrolled Subjects 
16.2.13.4 
Central Reader for MRI and CT Myelogram 
All Enrolled Subjects 
16.2.14.1 
Clinical Opiate Withdrawal Scale (COWS) 
All Enrolled Subjects 
16.2.14.2 
Subjective Opiate Withdrawal Scale (SOWS) 
All Enrolled Subjects 
16.2.15.1 
Exposure Summary - Dose Data 
All Enrolled Subjects 
16.2.15.2 
Exposure Summary - Pump Information 
All Enrolled Subjects 
16.2.15.3 
Exposure Summary - Dose Conversion 
All Enrolled Subjects 
 
 
 
 


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Appendix B 
 
The following two Memos-to-File document the closure of Site 028. 


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