Conditions: Chronic Pain
Keywords: Hydromorphone Hydrochloride Hydromorphone Pain Chronic Pain Implantable Pump Pump Intrathecal
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 364
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the long-term safety of hydromorphone hydrochloride administered by intrathecal delivery.

Detailed description:
This is an open-label, single-arm safety study to evaluate the safety of hydromorphone hydrochloride given by continuous intrathecal infusion using an implantable pump device. This study will enroll both subjects on a current opioid intrathecal medication as well as naïve subjects now current on intrathecal opioid medications. All subjects currently on intrathecal opioid treatment will be converted from their current intrathecal therapy to intrathecal hydromorphone hydrochloride according to standard medical practice. After an optimal dose for pain relief is achieved, subjects will remain on therapy for a total of 12 months or until discontinuation from the study. During this continuous dosing period, dose adjustments (up or down) are permitted to manage pain or side effects provided a maximum dose of 10 mg/day is not exceeded. Subjects will be assessed for pain intensity using a visual analog scale of pain intensity (VASPI) instrument at each study visit.

Subjects will be evaluated for side effects and clinical complications associated with the use of intrathecal hydromorphone. Events will be classified by intrathecal drugs used and concentrations.

Arms:
arm 1: Hydromorphone hydrochloride for intrathecal administration, 12 months safety evaluation

Interventions: intervention 1: Hydromorphone Hydrochloride intervention 2: Programmable Implantable pump
Intervention descriptions: intervention 1: Opioid for chronic pain intervention 2: Device: Programmable Implantable pump

Programmable Implantable pump delivering intrathecal hydromorphone

Protocol document:
Prot_000.pdf: 
MALLINCKRODT PHARMACEUTICALS, INC
INVESTIGATIONAL NEW DRUG PROTOCOL
INTRATHECAL HYDROMORPHONE HCL 10 MG/ML
PROTOCOL NUMBER CNS-HYD202US
VERSION 7.0 DATED 01 AUGUST 2016
AMENDMENT REVISING PRIOR VERSION 6.0 DATED 24 JUNE 2016
A Phase 3, Open-Label, Single-Arm Study To Assess The Safety Of 
Hydromorphone Hydrochloride Delivered By Intrathecal Administration
SPONSOR:
MALLINCKRODT PHARMACEUTICALS INC
675 MCDONNELL BLVD
HAZELWOOD, MO 63042
USA
CONFIDENTIAL


SUMMARY OF CHANGES FROM VERSION 6.0 TO VERSION 7.0
DATED 01 AUGUST 2016
This protocol amendment was required to allow dose adjustments immediately for subjects 
rolling over from the CNS-HYD201US study, to clarify that the study is open to all subjects in 
CNS-HYD201US who are randomized, or drop out prior to randomization, and the different 
procedures to be followed by subjects enrolling from CNS-HYD201US depending upon whether 
they were randomized subjects, or had dropped out prior to randomization. These and other 
changes are listed below:
1.  Version is changed from v6.0 to v7.0 and protocol re-dated as appropriate. Title page, headers 
and footers are revised appropriately.
2.  Protocol Synopsis, Study Design Section, last paragraph, was changed to allow dose 
adjustments from the beginning of enrollment, if clinically indicated.
3.  Protocol Synopsis, Study Design Section, last paragraph, was changed to clarify that those 
subjects dropping out of CNS-HYD201US prior to randomization will need to do all 
assessments in the CNS-HYD202US trial. Their assessments for CNS201 will not carry over.
4.  Section 1.4, Study Rationale, first paragraph, was revised to clarify that the CNS-HYD202US 
study is open to all subjects in CNS-HYD201US who are randomized, or drop out prior to 
randomization.
5.  Section 3.1, Description of Trial Design, eleventh paragraph, was revised to allow dose 
adjustments from the beginning of enrollment, if clinically indicated.
6.  Section 3.5.1.1, Titration to a Therapeutic Dose of Hydromorphone Hydrochloride was 
revised to allow dose adjustments from the beginning of enrollment, if clinically indicated.
7.  Section 9.2, Baseline Evaluations, third paragraph, was revised to clarify the different 
procedures to be followed by subjects enrolling from CNS-HYD201US depending upon 
whether they were randomized subjects, or had dropped out prior to randomization.
8.  Minor edits were made to correct grammar and spelling errors.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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CONFIDENTIAL
Table of Contents
LIST OF IN-TEXT TABLES......................................................................................................5
LIST OF APPENDICES .............................................................................................................6
LIST OF ABBREVIATIONS......................................................................................................7
1.0
INTRODUCTION..........................................................................................................16
1.1
Background.................................................................................................................16
1.2
Nonclinical Assessments.............................................................................................17
1.2.1
Pharmacology......................................................................................................17
1.2.2
Toxicology...........................................................................................................18
1.3
Clinical Experience.....................................................................................................19
1.3.1
Overview of Clinical Pharmacology.....................................................................19
1.3.2
Overview of Clinical Pharmacology.....................................................................20
1.3.3
Overview of Efficacy and Safety..........................................................................22
1.4
Study Rationale...........................................................................................................25
2.0
PURPOSE AND STUDY OBJECTIVES .......................................................................26
2.1
Purpose.......................................................................................................................26
2.2
Study Objectives.........................................................................................................26
2.2.1
Primary Objective................................................................................................26
3.0
STUDY DESIGN...........................................................................................................26
3.1
Description of Trial Design.........................................................................................26
3.2
Study Endpoints..........................................................................................................29
3.2.1
Primary Endpoint.................................................................................................29
3.2.2
Secondary Endpoints............................................................................................29
3.3
Diagnosis of an Inflammatory Granuloma...................................................................29
3.3.1
Treatment of an Inflammatory Granuloma ...........................................................30
3.4
Measures to Minimize Bias.........................................................................................31
3.4.1
Blinding...............................................................................................................31
3.4.2
Randomization/Assignment to Study Drug...........................................................31
3.5
Study Drugs................................................................................................................31
3.5.1
Rationale for Doses and Dosing Regimen ............................................................31
3.5.2
Dose Interruption.................................................................................................32
3.5.3
Pump or Catheter Replacements...........................................................................33


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Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
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3.6
Concomitant Medications............................................................................................33
3.6.1
Prior and Concomitant Medications .....................................................................33
3.6.2
Concomitant Medications Permitted to be Combined with Hydromorphone 
Hydrochloride in the Pump................................................................................................33
3.6.3
Prohibited Concomitant Medications ...................................................................34
3.7
Duration of Therapy....................................................................................................34
3.8
Procedures for Monitoring Subject Compliance ..........................................................34
4.0
STUDY POPULATION.................................................................................................35
4.1
Inclusion Criteria ........................................................................................................35
4.2
Exclusion Criteria .......................................................................................................35
5.0
SAFETY ASSESSMENTS.............................................................................................36
5.1
Collection of Adverse Events Data..............................................................................36
5.2
Physical Examinations and Medical History................................................................36
5.2.1
Complete Physical Examination...........................................................................36
5.2.2
Medical History ...................................................................................................36
5.3
Vital Signs and ECG...................................................................................................37
5.4
Documentation of Prior Concomitant Medications ......................................................37
6.0
PHARMACOKINETICS................................................................................................37
7.0
PHARMACODYNAMICS.............................................................................................37
8.0
EFFICACY ....................................................................................................................37
9.0
STUDY VISITS.............................................................................................................38
9.1
Screening....................................................................................................................38
9.2
Baseline Evaluations...................................................................................................38
9.3
Dose Titration Period (Optional Titration Days)..........................................................39
9.4
Long-Term Follow Up Period (Day 1 to Day 365) ......................................................40
9.5
Final Visit ...................................................................................................................40
10.0
PREMATURE DISCONTINUATION FROM STUDY..................................................40
11.0
PREMATURE DISCONTINUATION FROM STUDY DRUG......................................41
12.0
PRODUCT SPECIFICATIONS .....................................................................................41
12.1
Description..............................................................................................................41
12.2
Formulation, Packaging, and Labeling.....................................................................41
12.3
Receipt, Storage and Stability of Hydromorphone Intrathecal..................................42


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Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
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12.4
Preparation and Administration of Study Drug ........................................................42
12.5
Ordering and Distribution of Study Drug.................................................................42
12.6
Accountability of Study Drugs.................................................................................42
13.0
SAFETY MONITORING AND ADVERSE EVENTS...................................................43
13.1
Adverse Events........................................................................................................43
13.2
Serious Adverse Events ...........................................................................................45
13.2.1
Reporting Requirements for Serious Adverse Events ...........................................46
13.2.2
Recording of Serious Adverse Events ..................................................................47
14.0
STATISTICAL CONSIDERATIONS ............................................................................48
14.1
Sample Size Determination......................................................................................48
14.2
Analysis Data Sets...................................................................................................48
14.3
Safety Analysis........................................................................................................48
15.0
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE ............49
15.1
Data Collection and Reporting.................................................................................49
15.2
Study Monitoring ....................................................................................................49
15.3
Data Disclosure and Subject Confidentiality............................................................49
16.0
PROTECTION OF HUMAN SUBJECTS ......................................................................50
16.1
Declaration of Helsinki............................................................................................50
16.2
Institutional Review Board/Ethics Committee .........................................................50
17.0
REFERENCE LIST........................................................................................................51
18.0
SPONSOR SIGNATURE...............................................................................................64
LIST OF IN-TEXT TABLES
Table 13–1
Causality Categories for AE Descriptions ............................................................44
Table 13–2: Severity Assessment Terminology for Reporting Adverse Events (CTCAE v4.03) 45
Table 13-3
Reporting Requirements for Adverse Events........................................................47
Table 13–4: Contact Information for SAE Reporting.................................................................47
Table A-1: Schedule of Study Procedures .................................................................................55


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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CONFIDENTIAL
LIST OF APPENDICES
Appendix A: Schedule of Study Procedures ..............................................................................54
Appendix B: National Cancer Institute Common Terminology Criteria for Adverse Events ......57
Appendix C: Visual Analog Scale of Pain Intensity (VASPI)....................................................58
Appendix D: Clinical Opiate Withdrawal Scale (COWS) ..........................................................59
Appendix E: Brief Pain Inventory (BPI)....................................................................................61
Appendix F: Patient Global Impression of Change (PGIC)........................................................63


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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CONFIDENTIAL
LIST OF ABBREVIATIONS
ABBREVIATION
DEFINITION
AE
Adverse event
AUC
Area under the plasma concentration-time curve 
AUC0-∞
Area under the plasma concentration curve-time from time 0 to 
infinity
AUC0-t
Area under the plasma concentration-time curve from time 0 to 
the last quantifiable concentration
BPI
Brief Pain Inventory
CLcr
Creatinine Clearance
CFR
Code of Federal Regulations
cGMP
Current Good Manufacturing Practices
CMP
Complete Metabolic Panel 
CNS
Central Nervous System
COWS
Clinical Opiate Withdrawal Scale
CRF
Case Report Form
CRU
Clinical Research Unit
CSF
Cerebrospinal Fluid
CT
Computed Tomography
%cv
Percent Coefficient of Variation 
CTCAE
Common Terminology Criteria for Adverse Events (v. 4.03)
EC
Ethics Committee
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


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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CONFIDENTIAL
ABBREVIATION
DEFINITION
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
MFD
Maximum Feasible Dose
mg
Milligram
mL
Milliliter
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 
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-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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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 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 the Sponsor. The information contained 
herein is provided for the purpose of conducting a clinical trial for the Sponsor.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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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 the Sponsor.
__________________________________________
_______________________
Investigator’s Signature
Date


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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CONFIDENTIAL
PROTOCOL SYNOPSIS
Study title
A Phase 3, Open-Label, Single-Arm Study to Assess the Safety of Hydromorphone Hydrochloride
Delivered by Intrathecal Administration (CNS-HYD202US)
Sites
Up to 30
Study Drug 
Hydromorphone hydrochloride 2 mg/mL and 10 mg/mL
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: 
To evaluate the long-term (12-month) safety of a hydromorphone hydrochloride given by the intrathecal 
route of administration.
Study 
Design
This is an open-label, single-arm study to evaluate the safety of hydromorphone hydrochloride given by 
continuous intrathecal infusion using an implantable pump device. This clinical trial will be conducted at 
up to 30 clinical trial sites that are experienced with the use of intrathecal opioids. This study will enroll 
both subjects on a current opioid (eg, morphine or hydromorphone hydrochloride) intrathecal medication 
as well as naïve subjects not currently on intrathecal opioid medications. Dosing regimens allowed in this 
study will include simple continuous, complex continuous and Personal Therapy Manager (PTM) dosing.
For subjects entering the trial already on a therapeutic dose of hydromorphone hydrochloride, the 
hydromorphone hydrochloride will be replaced by the study drug (hydromorphone hydrochloride for 
intrathecal injection) on a 1:1 basis without dose adjustment or optional titration days. The subject is 
considered at a therapeutic dose and will start the study on Day 1.
Subjects converted from an intrathecal opioid therapy other than hydromorphone hydrochloride to the 
study drug will be dosed with the study drug according to the following conversion scheme:
Subject on Morphine or on another Opioid 3
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.
3 Convert the opioid to mg-morphine equivalent dose first. Then convert to hydromorphone hydrochloride based on mg-
morphine equivalent dose using the conversion scheme. 
Subjects who are converted directly to the study drug based on the 1:6 morphine-equivalence ratio are, by 
definition, at a therapeutic dose and must start the study on Day 1 without titration. Dose adjustments 
may be performed at subsequent visits, based on the investigator discretion.
For subjects converted using 1:12 conversion ratio, due to safety considerations, the conversion will be 
followed by up to five (5) optional titration days (Titration Days A, B, C, D and E) to achieve a 
therapeutic dose before starting Day 1. These optional titration days may be three (3) to fourteen (14) 
days apart.
In subjects receiving an intrathecal opioid in combination with another drug(s) prior to the enrollment of 
the study, the intrathecal opioid will be converted directly to the study medication (see the conversion 
scheme above) while the dose of the other drug(s) used in the combination should be kept the same.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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CONFIDENTIAL
Study 
Design 
(Continued)
The conversion will take place by removing the current intrathecal opioid therapy in the pump and then 
replacing the contents with study hydromorphone hydrochloride for intrathecal injection. At the 
discretion of the investigator the pump reservoir may be rinsed with preservative free sterile saline or 
study medication (hydromorphone hydrochloride for intrathecal injection). 
Dose adjustments may occur for any subject during the study, either on scheduled or unscheduled visit
after study Day 1, as needed 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 %
As needed, additional intrathecal concomitant medications may be added to the therapy to optimize pain 
control (see Section 3.6.2). 
Subjects who are naïve to intrathecal analgesics will have the pumps filled initially with a 2 mg/mL 
hydromorphone hydrochloride for intrathecal injection. Naïve subjects will be initiated on a dose between 
0.1 mg/day and 0.5 mg/day, based on their current opioid dose and the discretion of the investigator.
These subjects will be allowed up to five (5) optional titration days to achieve a therapeutic dose of 
hydromorphone prior to starting the long term safety period on Day 1 of this study. These optional 
titration days may be three (3) to fourteen (14) days apart. It is suggested that prior to a dose adjustment 
above 1 mg/day, the pump should be drained and refilled with 10 mg/mL hydromorphone hydrochloride 
and pump speed adjusted to achieve the target dose. Dose adjustments may continue as needed to 
optimize the therapy. After achieving a therapeutic dose of hydromorphone hydrochloride, additional 
intrathecal concomitant medications may be added to the therapy to optimize pain control for these 
subjects (see Section 3.6.2). 
Subjects continuing on therapy from the CNS-HYD201US trial may remain at their current dose of 
hydromorphone hydrochloride or may have a dose adjustment if clinically indicated, beginning at Day 1 
of this study. Subjects who were titrated off hydromorphone hydrochloride as part of the CNS-
HYD201US control arm will be titrated back to a therapeutic dose using one or more optional titration 
days prior to Day 1 of this study.
A maximum dose 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any time during 
this study. For subjects on PTM dosing regimens, the maximum daily dose will include the combined 
continuous dose and the allowed maximum PTM dose. All subjects should be contacted by telephone 24 
hours after initiating study medication of hydromorphone hydrochloride.
Subjects may be given FDA approved oral supplemental opioid medication and other FDA approved non-
opioid medications to help manage pain during the 12 month treatment.
Subjects will remain on therapy for a total of 12 months or until discontinuation from the study. During 
this continuous dosing period, dose adjustments (up or down) are permitted to manage pain or side effects
provided the maximum 10 mg/day dose of hydromorphone hydrochloride is not exceeded. All 
medications administered must be recorded. At no time may a contraindicated treatment (see Section
3.6.3) be administered in combination with hydromorphone hydrochloride. Subjects will be assessed for 
pain intensity using a VASPI instrument at each study visit.
Subjects will be evaluated for side effects and clinical complications associated with the use of intrathecal 
hydromorphone hydrochloride. Signs and symptoms of a suspected granuloma will be monitored; 
examples of these include but are not limited to radicular pain and loss of drug efficacy. 
If there are clinical signs or symptoms identified which may indicate an inflammatory mass formation, an 
MRI (with and without contrast) or CT myelogram should be performed (with consent of the subject) to 
evaluate the potential presence of a granuloma as opposed to other catheter related problems that may 
result in reduced delivery or clinical symptoms. Events will be classified by duration and concentration of 
intrathecal hydrophone hydrochloride. Events that may be related to a granuloma will be classified as 
confirmed granuloma or suspected granuloma.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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CONFIDENTIAL
Dosage and dose 
regimen
0.1 mg/day to 10 mg/day based on dose titration
Sample size
Approximately 350 subjects to be enrolled to complete at least 300 subjects with 6 months and 
100 subjects with 12 months of study drug treatment.
Duration of 
subject 
participation
Approximately 12 months
Study 
population
Subjects requiring intrathecal opioid treatment to manage chronic moderate-to-severe intractable pain, 
18 to 75 years of age.
Main Inclusion 
Criteria
Subjects must meet all of the following criteria to be included:
1.
Subjects must be at least 18 years of age and no more than 75 years old.
2.
Clinically diagnosed with moderate-to-severe intractable pain for at least a 6-month period.
3.
Subject is reasonably expected to benefit from intrathecal pain medication and has a SynchroMed 
II programmable intrathecal pump.
4.
Subject agrees to sign a Pain Treatment Agreement (Narcotic Contract) limiting narcotic 
prescriptions to the study medication prescribed by the investigator.
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 who can receive an MRI (with and without contrast) or CT myelogram.
8.
Provides written Ethics Committee approved informed consent.
9.
Willing to comply with all study procedures and requirements.
Main Exclusion 
Criteria
Subjects meeting any of the following criteria will be excluded:
1.
Women who are pregnant or breast-feeding
2.
Subject has any known or suspected allergy to hydromorphone hydrochloride or to the materials 
of the infusion pump or intrathecal catheter.
3.
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).
4.
Subjects who show signs of active systemic infection.
5.
Subjects with a metastatic cancer to the spinal canal or a known central nervous system 
contraindication to intrathecal therapy.
6.
Subjects have a condition requiring diathermy procedures.
7.
Subject has a life expectancy of less than 12 months.
8.
Subjects who are unable or unwilling to return to all of the required follow-up visits.
9.
As a result of medical review and physical examination, the Investigator considers the subject 
unfit for the study.


Mallinckrodt Pharmaceuticals, Inc
Protocol CNS-HYD202US
Intrathecal Hydromorphone Hydrochloride 
Version: 7.0
01 August 2016
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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. After signing an informed consent, and confirming eligibility and conformance with all 
entry criteria, the subject will be enrolled in the trial.
For trial subjects participating in the CNS-HYD201US trial only baseline assessments that are not 
already conducted as part of the CNS-HYD201US trial Day 119 or Study Termination assessments 
will be performed. However, those subjects dropping out of CNS-HYD201US prior to randomization 
will need to do all assessments and meet all subject selection criteria in the CNS-HYD202US trial. 
Their assessments for CNSHYD201US will not carry over.
Subjects entering the CNS-HYD202US study may either stay on their current hydromorphone 
hydrochloride therapy, be directly switched to hydromorphone hydrochloride from other opioid 
therapies, or will be titrated onto hydromorphone hydrochloride therapy as needed. Naïve subjects 
will need to be titrated to a therapeutic dose that is well tolerated prior to starting intrathecal
combination therapy. All other subjects on combination therapies may maintain their combination 
therapy regimen upon conversion to study medication. Subjects will return to the clinic according to
the schedule in Appendix A to have dose adjustments and study evaluations. For subjects converted to 
a hydromorphone hydrochloride equivalent dose based on a 1:12 ratio, who require titration prior to 
achieving a therapeutic dose of hydromorphone hydrochloride, up to five (5) optional titration days 
are allowed prior to starting Day 1 of the study. The subject may continue dose adjustments to 
optimize treatment during the 365 day continuous dosing period to evaluate long-term safety of 
intrathecal hydromorphone hydrochloride.
Study Duration
It is planned that each subject will participate in the study for approximately 12 months with expanded 
access after this period permitted at the discretion of the subject and attending physician and 
Mallinckrodt Pharmaceuticals. Overall duration of the study may be up to approximately 24 months 
not including the expanded access, depending on the rate of enrollment and number of subjects 
enrolled.
Safety 
Assessments
Subjects will be assessed throughout the study for adverse events and potential clinical signs and 
symptoms of a granuloma. Safety will be assessed through collection of AEs and SAEs during the 
conduct of the trial. At each visit, the subject will be queried for any AEs that differ from their 
baseline condition at the time of enrollment into the trial. 
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. In this study, the potential for a 
granuloma will be assessed at each visit to the investigator. If a granuloma is suspected based on 
clinical signs and symptoms, an MRI (with and without contrast) or CT myelogram should be 
obtained to evaluate if a granuloma is present. 
Clinical signs and symptoms that may indicate a granuloma include:

A sudden decrease in therapeutic response requiring increased daily doses that is not 
attributed to other assignable causes (eg, 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, confirmed granuloma is an intramural extra-medullary mass at the 
catheter tip that is confirmed by an MRI (with and without contrast) or CT myelogram as read by 
central independent radiologist, or by surgery. If only clinical signs are detected, but the granuloma or 
mass cannot be verified by MRI (with and without contrast) or CT myelogram, and no other cause can 
be determined, the event will be classified as a suspected granuloma. 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 an assessment of 
severity of the event and an opinion as to the cause.


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Primary 
Endpoint
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:

The rate of confirmed granulomas verified by MRI (with and without contrast), CT 
myelogram or by surgery.

The rate of suspected granulomas that cannot be verified by MRI (with and without 
contrast), CT myelogram or surgery. 
Secondary 
Endpoints
The following Secondary Endpoints will be assessed. Each of these endpoints will be evaluated at 
each study visit.

Change in the Visual Analog Scale Pain Intensity (VASPI) overtime.

Change in the Brief Pain Inventory (BPI) (1, 2) overtime.

Change in the Patient Global Impression of Change (PGIC) (3) overtime.
Statistical 
Methodology
Categorical data will be summarized by number and percentage. Continuous data will be 
summarized by sample size, mean, median, standard deviation, minimum value, and maximum 
value. No formal statistical testing is planned for this open-label safety trial. All data will be 
presented by study drug concentration (2 mg/mL and 10 mg/mL) and all subjects combined.
Subject disposition and demographics will be summarized. Safety will be evaluated based on 
incidence (number and percentage) of treatment-emergent AEs and SAEs summarized overall and 
by severity and by relationship to study treatment. Vital signs and vital sign changes will be 
analyzed as appropriate (with clinically meaningful vital sign abnormalities reported and analyzed 
as AEs). Incidence (number and percentage) and rate (including 95% confidence interval) of 
granuloma will be summarized for suspected and confirmed granulomas.
Study objectives will be met when 300 subjects complete 6 months and 100 subjects complete 12 
months of intrathecal hydromorphone therapy. For the purpose of the study report, the analyses 
may occur any time after the study submission objectives are met. At the time of submission, some 
subjects may still be receiving study treatment. Therefore, any subsequent safety data collected on 
those subjects will be submitted via a safety update, unless other format is requested by Regulatory 
Authorities.


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1.0
INTRODUCTION
1.1
Background
Hydromorphone hydrochloride is 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 
(4, 5). Dilaudid® was first marketed as an intravenous form of hydromorphone hydrochloride 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 
hydrochloride 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
hydrochloride 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 cGMP 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 hydrochloride 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 pharmacy-based compounding, pharmacy compounding or by manipulation of 
Dilaudid-HP® (hydromorphone hydrochloride for injection, approved for IV infusion), which 


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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-HYD202-US) is to support the safety of intrathecal 
hydromorphone hydrochloride given by continuous intrathecal administration using an 
implantable programmable intrathecal infusion pump. The results of this protocol will be used to 
support submission and approval of intrathecal hydromorphone hydrochloride 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%-40%. After intramuscular administration 
of hydromorphone, the analgesic onset is about 10-20 minutes, the time to peak analgesic effect 
is roughly 30-60 minutes, the analgesic duration is about 3-5 hours, and the elimination half-life 
is roughly 2-3 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 (eg, 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 
(eg, allodynia, myoclonus, seizures) (5).
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 (6). 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 (7).
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 
concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity 
occurred. (8). 


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Histamine release
Guedes et. al. found that intravenous hydromorphone hydrochloride induced minimal histamine 
release. They compared plasma histamine concentrations, behavioral and cardiovascular 
parameters following intravenous administration of hydromorphone hydrochloride 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 hydrochloride, 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 (9).
In conclusion, the analgesic properties and mechanism of action of intrathecal hydromorphone
hydrochloride as a potent agonist of the mu-opioid receptor is well understood and documented 
in the literature (4). The analgesic potency of hydromorphone hydrochloride 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 (10, 11). 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 (11). 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 (12).
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 increase53.
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. Subjects should seek medical attention if symptoms of adrenal 
insufficiency such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low 
blood pressure are experienced.
Long-term use of opioids may be associated with decreased sex hormone levels. Subjects should 
inform the study doctor if they experience signs or symptoms of low libido, impotence, erectile 
dysfunction, lack of menstruation, or infertility.
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 (eg, 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride has not been well evaluated in children.
Geriatric
The effect of age on the pharmacokinetics of hydromorphone hydrochloride has not been 
adequately evaluated.
Gender
Gender has little effect on the pharmacokinetics of hydromorphone hydrochloride. 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 hydrochloride use in 
subjects with intractable pain. These reports have also led to the common use of hydromorphone
hydrochloride in practice, with either compounded hydromorphone hydrochloride 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 hydrochloride
is discussed in an article by Lee et. al. (13) that evaluated literature in support of hydromorphone
hydrochloride, but concludes that the risk of unlicensed use of hydromorphone hydrochloride 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 hydrochloride, 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 (13-16).
A review article entitled “Hydromorphone for Acute and Chronic Pain” (16) reports data from 48 
studies (3510 participants). Of these studies 5 of the 48 studies were placebo-controlled, 43 of 48 
studies compared hydromorphone hydrochloride use with other opioids, bupivacaine and with 
itself with different formulations and routes of administration including intrathecal. The author 
concludes that hydromorphone hydrochloride appears to be a more potent analgesic, but that 
there is little difference between morphine and hydromorphone hydrochloride in terms of 
efficacy, adverse effect profile and subject preference. 
Other review articles also provide important data on the of intrathecal opioids, including 
hydromorphone hydrochloride (11, 12, 17-28). The use in children is also examined and provides 
some evidence of the effectiveness of intrathecal hydromorphone hydrochloride in the pediatric 
population (29). These articles also establish a conservatively safe starting dose for intrathecal 
hydromorphone hydrochloride 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 hydrochloride 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 hydrochloride
use and the efficacy in severe pain populations. The general conclusions presented were that 
intrathecal hydromorphone hydrochloride is safe and at least as effective as morphine, with the 
potential for some benefits.
Although there are no randomized controlled studies of hydromorphone hydrochloride
administered intrathecally, there are retrospective and prospective studies that have specifically 
examined the efficacy and safety of intrathecal hydromorphone hydrochloride alone or in 
combination (29-35). 


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Anderson et al (36) retrospectively reviewed 37 subjects with chronic nonmalignant pain 
managed with intrathecal hydromorphone hydrochloride after failure of intraspinal morphine. All 
subjects suffered from severe nonmalignant pain, most from failed lumbosacral spine operations 
(19/37; 51%). Morphine was replaced with hydromorphone hydrochloride 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 hydrochloride in most 
subjects. Peripheral edema was improved by hydromorphone hydrochloride but tended to recur 
with prolonged hydromorphone hydrochloride exposure. Analgesic response was improved by at 
least 25% in six of 16 subjects who were switched to hydromorphone hydrochloride because of 
poor pain relief. Du Pen et al (14) retrospectively reviewed 24 subjects with noncancer-related 
chronic pain receiving hydromorphone hydrochloride monotherapy. Average pain scores 
decreased significantly (p = 0.03).
Dominguez et al (37) found that half of 86 subjects in a retrospective review required either a 
switch to hydromorphone hydrochloride from morphine or adjuvants were added to morphine by 
18 months after initiation of intrathecal morphine therapy. Ackerman et. al. (33) retrospectively 
examined intrathecal clonidine and combination opioid/clonidine. Of 7 clonidine monotherapy 
treatment failure, 3 added hydromorphone hydrochloride, 1 of whom failed the combination 
therapy. Deer et al (35) retrospectively examined intrathecal ziconotide and opioid-ziconotide 
therapy. Seven of 16 subjects studied received hydromorphone hydrochloride. These 
retrospective studies confirm the common use of hydromorphone hydrochloride 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 hydrochloride versus morphine is 
that morphine induces histamine release while hydromorphone hydrochloride does not (37, 38).
This difference may be responsible for reports of decreased pruritus in subjects switched from 
morphine to hydromorphone hydrochloride (39). Potential improvements in other histamine-
related morphine adverse events such as peripheral vasodilation and hypotension by switching to 
hydromorphone hydrochloride 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 (9).
A metabolite of hydromorphone hydrochloride, hydromorphone-3-gucuronide, has been 
demonstrated to accumulate in chronic renal failure, perhaps producing neuropsychological 
effects including cognitive impairment (5, 40).
Case reports related to safety include a subject extracting hydromorphone hydrochloride from his 
pump (41), injection of hydromorphone hydrochloride into the subcutaneous pocket around the 
intrathecal pump (42), and a pontine hemorrhage following implantation of the pump and 


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initiation with hydromorphone hydrochloride /bupivacaine (43); 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) (44, 45) that, if undetected, can lead to irreversible neurological 
effects. Several review articles in the literature also evaluate the risk of mass formations or 
granulomas at the catheter tip with both morphine and hydromorphone hydrochloride (46-48).
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 (49) 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. (47) 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 hydrochloride. 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 hydrochloride, 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 (49). 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 (46). 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 (48). In animal studies, however, opiates at equianalgesic doses differ in the rate of 
granuloma formation (50, 51).
Granulomas have been reported most commonly with morphine. Other drugs have also been 
implicated in causing this complication, including hydromorphone hydrochloride, fentanyl, and 
tramadol (8, 51, 52). Animal studies in the sheep may indicate that at equivalent daily doses (eg,
10 mg/day) hydromorphone hydrochloride has less potential to induce an inflammatory mass or 
granuloma than morphine (18, 30). Given that hydromorphone hydrochloride is at least five-
times more potent than morphine, these observations may explain the belief of physicians that 
hydromorphone hydrochloride 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 
hydrochloride than morphine. Given 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 


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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 
included subjects receiving intrathecal morphine (Infumorph). Medtronic’s study was a careful 
examination of granuloma formation in subjects. A 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 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 hydrochloride use have not reported significant risk of granuloma 
formation. While there is no well-controlled trial with hydromorphone hydrochloride 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 hydrochloride, including 
the complication of drug dependency.
Based on the literature and wide spread use of off-label hydromorphone hydrochloride, there is 
potential that intrathecal hydromorphone hydrochloride 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 hydrochloride, 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 
hydrochloride to establish the efficacy and safety, as well as a cGMP 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 prospective, open-label, single-arm, Phase 3 clinical trial to be conducted at up to 30
clinical trial sites that are experienced with the use and management of implanted SynchroMed II 
pumps for intrathecal delivery of pain medications. The purpose of this study is to establish the 
long-term safety of a continuous intrathecal infusion of hydromorphone hydrochloride using a 


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programmable implantable pump in subjects with opioid resistant intractable pain. Subjects 
completing the CNS-HYD201US study as well as those subjects dropping out of 
CNS-HYD201US prior to randomization will be allowed to continue on long term follow-up 
therapy by enrollment in the CNS-HYD202US study. The study will also involve switching 
subjects from current opioid therapy per standard medical practice or titration of naïve subjects,
or those weaned off intrathecal treatment, onto hydromorphone hydrochloride therapy. 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 intrathecal pump or until the study is terminated after the 12-month 
safety evaluation.
This Phase 3 clinical trial is intended to provide safety data of a 2 mg/mL and 10 mg/mL 
Intrathecal hydromorphone hydrochloride given by the intrathecal route of administration for up
to 12 months in subjects with intractable pain.
2.0
PURPOSE AND STUDY OBJECTIVES
2.1
Purpose
The purpose of this clinical study is to demonstrate the long term 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.
2.2
Study Objectives
2.2.1
Primary Objective
To evaluate the long term (12-month) safety of a 2 mg/mL and 10 mg/mL intrathecal 
hydromorphone hydrochloride formulation given by the intrathecal route of administration.
3.0
STUDY DESIGN
3.1
Description of Trial Design
This is an open-label, single-arm study to evaluate the safety of hydromorphone hydrochloride 
given by continuous intrathecal infusion using an implantable pump device. This clinical trial 
will be conducted at up to 30 clinical trial sites that are experienced with the use of intrathecal 
opioids. This study will enroll both subjects on a current opioid (eg, morphine or hydromorphone
hydrochloride) intrathecal medication as well as naïve subjects not currently on intrathecal 
opioid medications. Dosing regimens allowed in this study will include simple continuous, 
complex continuous and Personal Therapy Manager (PTM) dosing.
For subjects entering the trial already on a therapeutic dose of another intrathecal 
hydromorphone hydrochloride, the hydromorphone hydrochloride will be replaced by the study 


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drug (hydromorphone hydrochloride for intrathecal injection) on a 1:1 basis without dose 
adjustment or optional titration days. The subject is considered at a therapeutic dose and will 
start the study on Day 1.
Subjects converted from an intrathecal opioid therapy other than hydromorphone hydrochloride 
to the study drug will be dosed with the study drug according to the following conversion 
scheme:
Subject on Morphine or on another Opioid 3
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.
3 Convert the opioid to mg-morphine equivalence dose first. Then convert to hydromorphone hydrochloride 
based on mg-morphine equivalent dose using the conversion scheme. 
Subjects who are converted directly to the study drug based on the 1:6 morphine-equivalence 
ratio are, by definition, at a therapeutic dose and must start the study on Day 1 without titration. 
Dose adjustments may be performed at subsequent visits, based on the investigator discretion.
For subjects using 1:12 conversion ratio, due to safety considerations, the conversion will be 
followed by up to five (5) optional titration days (Titration Days A, B, C, D and E) to achieve a 
therapeutic dose that is well tolerated before starting Day 1. These optional titration days may be 
three (3) to fourteen (14) days apart.
In subjects receiving an intrathecal opioid in combination with another drug(s) prior to the 
enrollment of the study, the intrathecal opioid will be converted directly to the study medication 
(see the conversion scheme above) while the dose of the other drug(s) used in the combination 
should be kept the same.
The conversion will take place by removing the current intrathecal opioid therapy in the pump 
and then replacing the contents with study hydromorphone hydrochloride for intrathecal 
injection. At the discretion of the investigator the pump reservoir may be rinsed with 
preservative free sterile saline or study medication (hydromorphone hydrochloride for intrathecal 
injection). 


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Dose adjustments may occur for any subject during the study, either on scheduled visits or 
unscheduled visits after study Day 1, as needed 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 %
As needed, additional intrathecal concomitant medications may be added to the therapy to 
optimize pain control (see Section 3.6.2). 
Subjects who are naïve to intrathecal analgesics will have the pumps filled initially with a 
2 mg/mL hydromorphone hydrochloride for intrathecal injection. Naïve subjects will be initiated 
on a dose between 0.1 mg/day and 0.5 mg/day, based on their current opioid dose and the 
discretion of the investigator. These subjects will be allowed up to five (5) optional titration days 
to achieve a therapeutic dose of hydromorphone prior to starting the long term safety period on 
Day 1 of this study. These optional titration days may be three (3) to fourteen (14) days apart. 
It is suggested that prior to a dose adjustment above 1 mg/day, the pump should be drained and 
refilled with 10 mg/mL hydromorphone hydrochloride undiluted and pump speed adjusted to 
achieve the target dose. Dose adjustments may continue as needed to optimize the therapy.
After achieving a therapeutic dose of hydromorphone hydrochloride, additional intrathecal 
concomitant medications may be added to the therapy to optimize pain control for these subjects 
(see Section 3.6.2). 
Subjects continuing on therapy from the CNS-HYD201US trial may remain at their current dose 
of hydromorphone hydrochloride or may have a dose adjustment if clinically indicated, 
beginning at Day 1 of this study. Subjects who were titrated off of hydromorphone hydrochloride 
as part of the CNS-HYD201US control arm will be titrated back to a therapeutic dose using one 
or more optional titration days prior to Day 1 of this study.
A maximum dose 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any time 
during this study. For subjects on PTM dosing regimens, the maximum daily dose will include 
the combined continuous dose and the allowed maximum PTM dose. All subjects should be 
contacted by telephone 24 hours after initiating study medication of hydromorphone 
hydrochloride.
Subjects may be given FDA approved oral supplemental opioid medication and other FDA 
approved non-opioid medications to help manage pain during the 12 month treatment.
Subjects will remain on therapy for a total of 12 months or until discontinuation from the study. 
During this continuous dosing period, dose adjustments (up or down) are permitted to manage 
pain or side effects provided the maximum 10 mg/day dose of hydromorphone hydrochloride is 


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not exceeded. All medications administered must be recorded. At no time may a contraindicated 
treatment (see Section 3.6.3) be administered in combination with hydromorphone 
hydrochloride. Subjects will be assessed for pain intensity using a VASPI instrument at each 
study visit.
Subjects will be evaluated for side effects and clinical complications associated with the use of 
intrathecal hydromorphone hydrochloride. Signs and symptoms of a suspected granuloma will be 
monitored; examples of these include but are not limited to radicular pain and loss of drug 
efficacy. 
If there are signs or symptoms identified which may indicate an inflammatory mass formation, 
an MRI (with and without contrast) or CT myelogram will be performed (with consent of the 
subject) to evaluate the potential presence of a granuloma as opposed to other catheter related 
problems that may result in reduced delivery or clinical symptoms. Events will be classified by 
duration, and concentration of intrathecal hydromorphone hydrochloride. Events that may be 
related to a granuloma will be classified as confirmed granuloma or suspected granuloma.
3.2
Study Endpoints
3.2.1
Primary Endpoint
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:

The rate of confirmed granulomas verified by MRI (with and without contrast), 
CT myelogram or by surgery.

The rate of suspected granulomas that cannot be verified by MRI (with and without 
contrast), CT Myelogram or surgery.
3.2.2
Secondary Endpoints
The following secondary endpoints will be assessed. Each of these endpoints will be evaluated at 
each study visit.

Change in Visual Analog Scale Pain Intensity (VASPI) over time.

Change in the Brief Pain Inventory (BPI) (1, 2) over time.

Change in the Patient Global Impression of Change (PGIC) (3) over time.
3.3
Diagnosis of an Inflammatory 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 
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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 (eg, 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.
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 contrast) or CT myelogram will be 
requested. All MRIs (with and without contrast) and CT myelograms will be assessed by a single 
central independent radiologist who will be blinded to the subject’s history. The criteria used by 
the primary investigator to detect a potential granuloma will be recorded.
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 and be confirmed by an independent blinded radiologist. If only clinical signs are 
detected, but the granuloma or mass cannot be verified by MRI (with and without contrast) or 
CT myelogram, and no other cause can be determined, the event will be classified as a suspected 
granuloma.
3.3.1
Treatment of an Inflammatory Granuloma
If a granuloma is detected early in its clinical course, depending upon an individual subject's 
clinical condition, intra-spinal 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. 
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 intra-spinal 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


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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 an open-label, single-arm safety trial. As such there is no blinding.
3.4.2
Randomization/Assignment to Study Drug
Each subject entered into the trial will be assigned a subject number consisting of a two-digit site 
number and three-digit sequential subject number (SS-XXX). This number will be used for the 
entire duration of the trial. There is no randomization in this trial.
3.5
Study Drugs
3.5.1
Rationale for Doses and Dosing Regimen
3.5.1.1
Titration to a Therapeutic Dose of Hydromorphone Hydrochloride
For subjects entering the trial already on a therapeutic dose of another intrathecal 
hydromorphone hydrochloride, the hydromorphone hydrochloride will be replaced by the study 
drug (hydromorphone hydrochloride for intrathecal injection) on a 1:1 basis without dose 
adjustment or optional titration days. The subject is considered at a therapeutic dose and will 
start the study on Day 1.
Subjects who are converted directly to the study drug based on the 1:6 morphine-equivalence 
ratio are, by definition, at a therapeutic dose and must start the study on Day 1 without titration
Dose adjustments may be performed at subsequent visits, based on the investigator discretion 
(see Section 3.1). 
For subjects converted using the 1:12 ratio, due to safety considerations, the conversion will be 
followed by up to five (5) optional titration days (Titration Days A, B, C, D and E) to achieve a 
therapeutic dose before starting Day 1. These optional titration days may be three (3) to fourteen 
(14) days apart.
The conversion will take place by removing the current intrathecal opioid therapy in the pump 
and then replacing the contents with study hydromorphone hydrochloride for intrathecal 
injection. At the discretion of the investigator the pump reservoir may be rinsed with 
preservative free sterile saline or study medication (hydromorphone hydrochloride for intrathecal 
injection). 
Subjects who are naïve to intrathecal analgesics will have the pumps filled initially with a 
2 mg/mL hydromorphone hydrochloride for intrathecal injection. Naïve subjects will be initiated 
on a dose between 0.1 mg/day and 0.5 mg/day, based on their current opioid dose and the 


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discretion of the investigator. These subjects will be allowed up to five (5) optional titration days 
to achieve a therapeutic dose of hydromorphone prior to starting the long term safety period on 
Day 1 of this study. These optional titration days may be three (3) to fourteen (14) days apart.
Prior to a dose adjustment above 1 mg/day, the pump should be drained and refilled with 
10 mg/mL hydromorphone hydrochloride undiluted and pump speed adjusted to achieve the 
target dose. Dose adjustments may continue as needed to optimize the therapy. After achieving a 
therapeutic dose of hydromorphone hydrochloride, other permitted drug products 
(see Section 3.6.2) may be added to the pump to optimize analgesia for these subjects if needed. 
Subjects continuing on therapy from the CNS-HYD201US trial may remain at their current dose 
of hydromorphone hydrochloride or may have a dose adjustment if clinically indicated, 
beginning at Day 1 of this study. Subjects who were titrated off of hydromorphone hydrochloride 
as part of the CNS-HYD201US control arm will be titrated back to a therapeutic dose using one 
or more optional titration days prior to Day 1 of this study.
A maximum dose 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any time 
during this study. For subjects on PTM dosing regimens, the maximum daily dose will include 
the combined continuous dose and the allowed maximum PTM dose. All subjects should be 
contacted by telephone 24 hours after initiating study medication of hydromorphone 
hydrochloride.
3.5.1.2
12-Month Course of Treatment
After the initial titration period, if needed, subjects will start on Day 1 of this trial and remain on 
therapy for an additional 365 days of hydromorphone hydrochloride treatment. After the initial 
titration and during the 365 day continuous dosing period run in period, dose adjustments are 
permitted either upward or down as deemed necessary by the investigator, provided that the 
maximum dose of 10 mg/day is not exceeded. During this long term evaluation period subjects 
will visit the clinic as outlined in the Schedule of Events (Appendix A) for evaluations, but may 
come back sooner if necessary to adjust the daily dose or for any safety related reason.
As needed, additional concomitant medications and intrathecal therapies may be added to the 
therapy to optimize pain control of the compound and dose (see Section 3.1).
3.5.2
Dose Interruption
Unscheduled dose interruptions are permitted on this clinical trial as deemed necessary by the 
investigator. If a dose interruption occurs this should be recorded and reason for the interruption 
documented. Dose interruptions are permitted up to 14 days to correct mechanical issues with the 
pump or catheter, as well as pump replacements if necessary. Supportive oral, intravenous or 
transdermal medication may be given to manage pain and withdrawal symptoms at the discretion 
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3.5.3
Pump or Catheter Replacements
Pump or catheter replacements are permitted in this trial due to mechanical malfunctions, battery 
failures or other related mechanical reasons. The Medical Monitor should be notified if any 
subject requires a surgical procedure to correct a catheter failure or requires a pump replacement.
If a subject requires a pump replacement or catheter replacement, drug interruptions for up to 14
days are permitted while the procedure is conducted and study drug can be replaced into the new 
pump. If the pump is removed, drug within the pump should be discarded and replaced with 
investigational product from a new vial(s) of hydromorphone hydrochloride. Investigational drug 
wasted from the pump should be documented for accurate drug accountability. After the pump or 
catheter replacement, at the discretion of the investigator, subjects may be restarted at their 
previous dose of hydromorphone hydrochloride or a reduced dose and titrated back to a 
therapeutic dose as part of normal standard of care for that subject after the pump or catheter 
replacement.
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. 
While there is minimal published systematic experience with the use of intrathecal 
hydromorphone hydrochloride in combination with other medications the practice of giving 
combinations of products in intrathecal pumps to manage pain symptoms is common.
Physiological interactions attributed to the combined use of intrathecal hydromorphone
hydrochloride and other epidural analgesics may include excessive sedation, hypotension and 
respiratory depression.
3.6.2
Concomitant Medications Permitted to be Combined with Hydromorphone 
Hydrochloride in the Pump
If additional therapeutic agents are needed to achieve optimal analgesic effect, it is permissible to 
use a concomitant medication added to the hydromorphone hydrochloride to be used through the 
intrathecal route. Naïve subjects will need to be titrated to a therapeutic dose that is well 
tolerated prior to starting intrathecal combination therapy. All other subjects on combination 
therapies may maintain their combination therapy regimen upon conversion to study medication.
A list of drugs commonly combined with hydromorphone hydrochloride and administered 
through intrathecal pumps is provided below:


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
Bupivacaine

Fentanyl

Clonidine

Baclofen

Gabapentin

Ropivacaine
Other concomitant medications should be avoided during the conduct of this study.
3.6.3
Prohibited Concomitant Medications
During treatment with intrathecal hydromorphone hydrochloride, subjects should avoid 
sedatives, hypnotics, phenothiazines, anesthetics, tranquilizers or other drugs that may induce 
hypotension or depressive effects. Subjects should be advised to avoid excessive alcohol 
consumption while on therapy. 
Agonist/antagonist analgesics (i.e. 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 caution53.
3.7
Duration of Therapy
In the absence of a granuloma or intolerable related AEs (Adverse Drug Reactions) subjects in 
this trial may continue on treatment for approximately 365 days after Day 1 of this trial.
3.8
Procedures for Monitoring Subject Compliance
Subjects will return to the clinic for scheduled visits and pump refills as specified in 
Appendix A, but pumps may be filled sooner if necessary or for scheduling purposes.
Subjects who do not comply with the visit schedule will be discontinued from the study, weaned 
off study medication, and can receive another treatment at the discretion of the attending 
physician caring for the patient.


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4.0
STUDY POPULATION
Male or female subjects requiring intrathecal opioid treatment to manage chronic moderate-to-
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. Subjects must be at least 18 years of age and no more than 75 years old.
2. Clinically diagnosed with moderate-to-severe intractable pain for at least a 6-month 
period.
3. Subject is reasonably expected to benefit from intrathecal pain medication and has a 
SynchroMed II programmable intrathecal pump.
4. Subject agrees to sign a Pain Treatment Agreement (Narcotic Contract) limiting narcotic 
prescriptions to the study medication prescribed by the investigator.
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 who can receive an MRI (with and without contrast) or CT myelogram.
8. Provides written Ethics Committee approved informed consent.
9. 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 breast-feeding.
2. Subject has any known or suspected allergy to hydromorphone hydrochloride or to the 
materials of the infusion pump or intrathecal catheter.
3. 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).
4. Subjects who show signs of active systemic infection.
5. Subjects with a metastatic cancer to the spinal canal or a known central nervous system 
contraindication to intrathecal therapy.
6. Subjects have a condition requiring diathermy procedures.
7. Subject has a life expectancy of less than 12 months.
8. Subjects who are unable or unwilling to return to all of the required follow-up visits.
9. As a result of medical review and physical examination, the Investigator considers the 
subject unfit for the study.


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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, during 
optional titration days, and for the long-term safety period starting on Study Day 1 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, 
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.
All abnormal changes from baseline in physical examination findings including 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 a complete physical examination at screening. Results 
will be recorded as part of the Medical History. 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
A medical history will be obtained at screening. For subjects entering the CNS-HYD202US trial 
from the CNS-HYD201US trial, medical history will be imported from the previous trial and 
does not have to be repeated.
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 


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in severe intractable pain requiring an intrathecal pump will be obtained and recorded in the 
CRF:

Underlying disease, injury or condition resulting in intractable pain, date of initial 
diagnosis, and prior treatments.

Date of implantation of an intrathecal SynchroMed II 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
Vital Signs and ECG
Systolic and diastolic blood pressure, radial pulse, breathing rate and temperature will be 
obtained at baseline and each study visit and recorded. All vital signs will be obtained in a semi-
recumbent position.
An ECG will also be obtained at screening to assess any cardiovascular abnormalities for the 
purposes of determining eligibility for this trial.
5.4
Documentation of Prior Concomitant Medications
Details regarding the name, indication, dose, route of administration, and frequency of all 
prescription medications within the past 30-days will be recorded. For subjects entering the 
CNS-HYD202US trial from the CNS-HYD201US trial, medical history will be imported from 
the previous trial and does not have to be repeated.
6.0
PHARMACOKINETICS
No pharmacokinetic assessments will be conducted during this trial.
7.0
PHARMACODYNAMICS
Other than pain evaluation, no pharmacodynamic assessments are planned during this trial.
8.0
EFFICACY
There is no efficacy endpoint in this trial given the open-label nature of the study. Subjects will 
be given a VASPI at scheduled time periods and generally during visits to the clinical site.


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9.0
STUDY VISITS
Refer to Appendix A for the Schedule of Study Procedures.
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
that are not considered standard of care assessments. The signature, date, and the name of the 
individual(s) who obtained the informed consent will be recorded in the subject’s medical record. 
Screening, baseline, and initiation of dosing (Day 1 or optional titration day) may be combined 
as one visit for this trial. Laboratory testing is obtained as part of the baseline status of the 
subject for future adverse event evaluation, however, laboratory test results are not required for 
entry criteria and thus the subject may be enrolled prior to results being obtained.
For subject entering this trial from the CNS-HYD201US trial, informed consent may be obtained 
up to 30-days prior to the transition to this study. Screening, baseline and Day 1 assessments for 
this trial will be conducted as part of the final visit of the CNS-HYD201US study as indicated in 
Appendix A. Subjects transitioning from the CNS-HYD201US trial will retain their subject 
number from that study for the long-term safety trial.
For all other subjects not transitioning from CNS-HYD201US, after written informed consent is 
obtained, the subject will be assigned a subject number (SS-XXX) by the site and will undergo 
the designated screening procedures listed in Appendix A within 14 days prior to initiation of 
weaning or start of 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. Screening procedures may be combined with 
baseline assessments and enrollment (Day 1 or optional titration day) in this trial.
9.2
Baseline Evaluations
If the subject is determined to be eligible for participation in the study they will undergo baseline 
assessments prior to study drug administration. Baseline assessments will be conducted 
according to the procedures outlines in Appendix A.
Note that the Screening, Baseline and/or the first day of dosing (enrollment) may be combined at 
one visit.
Note that for randomized subjects entering the CNS-HYD202US trial from the 
CNS-HYD201US trial, a physical examination and vital signs will be completed on the final 
visit day of the CNS-HYD201US trial, which is Day -1 of the CNS-HYD202US trial. However, 


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those subjects dropping out of CNS-HYD201US prior to randomization will need to do all 
assessments and meet all subject selection criteria in the current trial. Their assessments for 
CNSHYD201US will not carry over.
9.3
Dose Titration Period (Optional Titration Days)
Subjects requiring dose titration onto hydromorphone hydrochloride for injection will return to
the investigational site every 3 to 14 days for dose adjustments. These dose adjustment days are 
considered Optional Titration days in the Schedule of Study Procedures (Appendix A).
Subjects who are not participating in the CNS-HYD201US trial, and are naïve to intrathecal 
medications or have been weaned off current intrathecal medications, will have the pumps filled 
initially with a 2 mg/mL hydromorphone hydrochloride for intrathecal injection. Subjects 
requiring titration from a low dose will be initiated on a dose between 0.1 mg/day and 
0.5 mg/day, based on their current oral opioid dose and at the discretion of the investigator.
These subjects will be allowed up to five (5) Optional Titration periods to achieve a therapeutic 
dose of hydromorphone prior to starting the long term safety period on Day 1 of this study. Dose 
adjustments thereafter will be allowed at regular scheduled visits by adjusting the pump speed 
with a maximum dose adjustment of 50% for doses up to 0.5 mg/day and 25% for doses above 
0.5 mg/day.
For subjects who are entering this study from the CNS-HYD201US trial or who are converting 
directly from compounded hydromorphone hydrochloride (eg, Dilaudid®), the starting dose will 
be based on their prior dose. For subjects who have been weaned off therapy or are at a dose 
below what is considered adequate to treat their chronic pain, or are on other Intrathecal opioids, 
will need to be switched to hydromorphone hydrochloride Intrathecal Injection first and may 
require one or more Optional Titration days (See Schedule of Study Events in Appendix A).
Once a dose that achieves adequate pain relief is determined, the subject will start at Day 1 of 
this study and continue per the Schedule of Study Events. Dose adjustments thereafter will be
allowed at regular scheduled visits by adjusting the pump speed with a maximum dose 
adjustment of 50% for doses up to 0.5 mg/day and 25% for doses above 0.5 mg/day.
Prior to a dose adjustment above 1 mg/day, the pump should be drained and refilled with 
10 mg/mL hydromorphone hydrochloride undiluted and pump speed adjusted to achieve the 
target dose. Dose adjustments may continue as needed to optimize the therapy. It is 
recommended that naïve subjects that are titrated onto hydromorphone hydrochloride be 
maintained on a monotherapy until on a therapeutic dose of hydromorphone hydrochloride. After 
titration and stabilization, other drugs may be included in the intrathecal pump (see 
Section 3.6.2) as part of the therapy if judged necessary by the primary investigator.
Oral opioid medication may be prescribed as needed during the dose titration phase. Other FDA 
approved non-opioid oral pain medications are permitted during this period in accordance with 
their marketed product labeling.


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9.4
Long-Term Follow Up Period (Day 1 to Day 365)
After the titration period (if required based on the investigators discretion) subjects will start Day 
1 of this trial and remain on continuous intrathecal treatment for the next 365 days or until 
withdrawal from the trial. Subjects may have their dose of intrathecal hydromorphone 
hydrochloride adjusted upwards or downwards during this period as necessary to obtain optimal 
pain relief and manage side effect, provided the dose does not exceed 10 mg/day (eg, 1.0 mL/day
of 10 mg/mL hydromorphone hydrochloride for injection). Oral opioid supplemental medication 
may be prescribed as necessary and appropriate according to the practice of medicine. As needed 
other intrathecal medications (see Section 3.6.2) may also be added as deemed appropriate by the 
investigator with the drug generic name and daily dose recorded. Other FDA approved nonopioid 
oral pain medications are permitted during this period in accordance with their marketed product 
labeling. 
Study procedures and assessments during this period are conducted according to Appendix A.
Pump refills during this period are conducted as needed to maintain the appropriate volume of 
product in the pump and maintain the subject dosing. Additional unscheduled visits for dose 
adjustments, titration or to assess potential complications are permitted as needed.
All visit dates during the long term follow-up period are to be conducted within 7 days of the 
scheduled date (ie, ± 7 days).
9.5
Final Visit
Subjects will return to the investigational site for the final visit at approximately Day 365
(12 months after long term treatment starts) or when discontinued from the study for any reason.
At the final study visit subjects will be assessed for AEs and clinical signs or symptoms of a 
granuloma as well as other procedures according to Appendix A. At the final study visit, the 
investigator will remove the residual study drug from the subject’s pump and will replace the 
study drug with standard of care medication/therapy.
10.0
PREMATURE DISCONTINUATION FROM STUDY
A subject may be involuntarily discontinued from the study for the following reasons, at the 
discretion of the investigator and the Sponsor: 

Noncompliance with study procedures and visits to the investigational site

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.


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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. If subjects are discontinued, they will be titrated off of hydromorphone hydrochloride
therapy and placed on other alternative treatments at the discretion of the investigator and 
according to standard medical practice and manufacturer instructions for the intrathecal pump.
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 (or designee) must complete all applicable CRF pages for subjects who 
discontinue study drug prematurely. Final visit procedures (See Appendix A) should be 
conducted for any subject who discontinues study drug prematurely.
Subjects who prematurely discontinue study drug for any reason other than toxicity may be re-
entered into the study after consultation between the Investigator and the Sponsor or the 
Sponsor’s designee. Dosing of a subject who previously discontinued in the study is at the 
discretion of the Sponsor. However, subjects who drop out due to toxicity will not be replaced.
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 (2,000 mcg/mL) or 200,000 mcg per 20 mL 
(10,000 mcg/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. Vials will be 
packaged in boxes 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)


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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) 2 mg/mL and 10 mg/mL vials will be 
packaged in boxes for shipment to investigational sites. During shipment excursions are
permitted to 4to 30C (39° to 86°F), and after receipt drug should be stored at 15° to 30°C
(59° to 86°F) until use. Excursions from the temperature storage condition should be reported to 
the study monitor.
12.4
Preparation and Administration of Study Drug
There is no manipulation or preparation of study drug other than filling into the intrathecal 
programmable infusion pump according to the manufacturer’s instructions.
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. The study drug must be stored in a restricted area with limited access. 
Contents of the study drug containers must not be combined.


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The Investigator must maintain an accurate, up to date Dispensing Log for all study drugs 
supplied by the Sponsor. The study drug Dispensing Log and remaining drug inventory will be 
reviewed at each monitoring visit by the Sponsor-designated clinical monitor.
Study drug dispensed for all subjects must be recorded on subject specific Drug Accountability 
Log.
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.
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.
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 in the CRF 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 (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.


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The reporting period for AEs starts after the first administration of study drug on Day 1 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.
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”. 
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) v4.03. The investigator will determine the 
severity of each AE based on CTCAE criteria and will record the grade of the event on the 
source documents and AE CRF. 


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In order to classify adverse events and diseases, preferred terms will be assigned by the sponsor 
or its designee to the original terms entered on the CRF, using MedDRA. CTCAE is provided in
Appendix B. 
Table 13–2: Severity Assessment Terminology for Reporting Adverse Events 
(CTCAE v4.03)
CTCAE Grade
Common Term
Description
1
Mild
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
2
Moderate
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living 
(ADL).
3
Severe
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of
hospitalization indicated; disabling; limiting self care Activities 
of Daily Living (ADL).
4
Life-
Threatening
Life-threatening consequences; urgent intervention indicated.
5
Death
Outcome of AE was death
For those AEs that are not described on the CTCAE v4.03, 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.


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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.
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. 


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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.
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 (eg, 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.


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14.0
STATISTICAL CONSIDERATIONS
14.1
Sample Size Determination
This study is planned to enroll approximately 350 subjects at up to thirty (30) investigative sites
to obtain 300 subjects completing 6-months and 100 subjects completing 12-months of 
intrathecal hydromorphone hydrochloride therapy. Additional subjects may be enrolled as 
deemed necessary to reach the study completion requirements for subjects on long term 
intrathecal hydromorphone hydrochloride therapy. 
14.2
Analysis Data Sets
Subjects who receive at least one day of hydromorphone hydrochloride intrathecal treatment will 
be included in the safety analyses.
14.3
Safety Analysis
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.
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.
The incidence (number and percentage) and rate (including 95% confidence interval) of 
granuloma will be summarized for suspected and confirmed granulomas.
Study objectives will be met when 300 subjects complete 6 months and 100 subjects complete 
12 months of intrathecal hydromorphone therapy. For the purpose of the study report, the 
analyses may occur any time after the study submission objectives are met. At the time of 
submission, some subjects may still be receiving study treatment. Therefore, any subsequent 
safety data collected on those subjects will be submitted via a safety update, unless a different
format is requested by regulatory authorities.


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15.0
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE
15.1
Data Collection and Reporting
A CRF will be completed for each subject assigned a study number, ICF and receives at least one 
dose of study drug. All entries on the CRF must be supported by original source documentation 
(eg, laboratory reports, medical records) maintained at the investigational site. 
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 on the CRF 
and 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 source documents, CRFs, etc., for review and inspection by the clinical 
monitor.
All CRFs will be 100% source verified against corresponding source documentation (eg, 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 the source documents and the CRFs. Clinical 
monitors will also ensure that all protocol requirements, applicable FDA regulations, other 
requirements, and Investigator’s obligations are being fulfilled.
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 clinical monitor (or 
designee), and the IRB/EC.
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 kept in a 
locked file cabinet. All computer entry and networking programs will be identifiable only by 
coded numbers. Clinical information will not be released without written permission from the 


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subject, except as necessary for monitoring by the IRB, the FDA, or the study Sponsor clinical 
monitor (or designee). 
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.
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Dimensions of the impact of cancer pain in a four country sample: new information from 
multidimensional scaling. Pain. 1996;67(2-3):267-73.
2.
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.
3.
W. G. ECDEU assessment manual for psychopharmacology Rockville, MD: U.S. 
National Institute of Health, Psychopharmacology Research Branch; 1976.
4.
Murray A, Hagen NA. Hydromorphone. Journal of pain and symptom management. 
2005;29(5 Suppl):S57-66.
5.
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.
6.
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.
7.
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.
8.
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.
9.
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.
10.
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 
of chronic central pain after spinal cord injury. Brain research. 2000;859(1):72-82.
11.
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 
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hydromorphone added to hyperbaric bupivacaine for postoperative pain relief after knee 
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anaesthesiology. 2012;29(1):17-21.
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pain: a retrospective study. Pain Med. 2006;7(1):10-5.
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17.
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.
18.
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.


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19.
Newsome S, Frawley BK, Argoff CE. Intrathecal analgesia for refractory cancer pain. 
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review of the literature on intrathecal delivery of pain medication. Journal of pain and symptom 
management. 2000;20(2):S12-36.
21.
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.
22.
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.
23.
Walker SM, Goudas LC, Cousins MJ, Carr DB. Combination spinal analgesic 
chemotherapy: a systematic review. Anesthesia and analgesia. 2002;95(3):674-715.
24.
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.
25.
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research. 2009;2:135-55.
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intraspinal infusions of opioids in the treatment of neuropathic pain. Journal of pain and 
symptom management. 1995;10(7):527-43.
27.
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.
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noncancer pain: a systematic review and meta-analysis of efficacy and safety. Journal of pain 
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29.
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.
30.
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Safety of chronic intrathecal morphine infusion in a sheep model. Anesthesiology. 
2003;99(1):188-98.
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ziconotide and opioid combination therapy for noncancer pain: an observational study. Pain 
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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 


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chronic non-cancer pain patients. Pain practice : the official journal of World Institute of Pain. 
2002;2(4):315-25.
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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.
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human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology. 
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hydrochloride. Journal of pain and symptom management. 1999;17(1):70-2.
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fentanyl anesthesia. Anesthesiology. 1982;56(2):93-6.
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Babul N, Darke AC, Hagen N. Hydromorphone metabolite accumulation in renal failure. 
Journal of pain and symptom management. 1995;10(3):184-6.
43.
Kittelberger KP, Buchheit TE, Rice SF. Self-extraction of intrathecal pump opioid. 
Anesthesiology. 2004;101(3):807.
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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.
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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.
46.
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.
47.
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.
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Ramsey CN, Owen RD, Witt WO, Grider JS. Intrathecal granuloma in a patient receiving 
high dose hydromorphone. Pain physician. 2008;11(3):369-73.
49.
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.
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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.
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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.
52.
Allen JW, Horais KA, Tozier NA, Yaksh TL. Opiate pharmacology of intrathecal 
granulomas. Anesthesiology. 2006;105(3):590-8.
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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


Appendix A: Schedule of Study Procedures


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Table A- 1: Schedule of Study Procedures
Study Procedure
Visit Schedule
Study Daya
Screening
Days -14 
to 1b
Baseline
Days -3 
to 1b
Baseline 
for
HYD201US
Subjectsb
Optional 
Titration 
Daysb,c
Day
1b,d
Day
28
Day
56
Day
80
Day
104
Day
160
Day
216
Day
286
Final 
Study 
Visit
Day 
365
Signed Informed Consent
Xe
X
Medical Historyf
X
*
Complete physical examg
X
*
X
Vital signs and Weightg
X
X
*
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test g
X
X
X
X
ECGg
X
X
CBC, CMP, Urinalysisg
X
X
Concomitant medication assessment
X
X
*
X
X
X
X
X
X
X
X
X
X
Adverse event assessment
X
X
*
X
X
X
X
X
X
X
X
X
X
Hydromorphone Hydrochloride
Pump Dose Adjustment and Refills h,I,l
X
X
X
X
X
X
X
X
X
X
Xl
Oral Opioid
X -----------------------------------------------------------------------------------------------------------------
Clinical evaluation for Granulomasj
X
*
X
X
X
X
X
X
X
X
X
VASPI Assessmentk
X
X
*
X
X
X
X
X
X
X
X
X
X
COWS Assessmentk
X
*
X
X
BPIk
X
*
X
X
X
X
X
PGICk
X
*
X
X
X
X
X
a.
Study Day is based on Day 1 defined as the first day a subject achieves a therapeutic dose of hydromorphone therapy. There is no Day 0 in this trial. Optional titration days for subjects below 
therapeutic levels will not be counted towards the 365 day study period. All visit days are +/- 7 days during the long-term extension phase of the study. Additional unscheduled visits may be 
scheduled to make dose adjustments or prescribe oral medication to manage pain and withdrawal symptoms as deemed appropriate by the investigator.
b.
Screening period is 14 days. Screening, Baseline and/or Initiation of Dosing (ie, Optional Titration Day or Day 1) visits may be combined. For subjects entering the CNS-HYD202US clinical trial 
that are transitioning from the CNS-HYD201US efficacy trial, these subjects will not be required to repeat Screening. For these subjects the last day of the CNS-HYD201US trial will be 
considered the first day (either optional titration day or Day 1) of the CNS-HYD202US trial. Baseline assessments will be completed as part of the final day (Day 119 or Treatment Failure day) and 
only additional activities or tests shown on the Schedule of Events (shown in table of events as “X”) for these subjects are required to enter the CNS-HYD202US trial. Tests that are done as part of 
the final visit of the CNS-HYD201US trial and will not be repeated in this study are shown in the table with a “*”.
c.
Optional titration days are intended for subjects requiring titration after switching from other opioids or control arm subjects enrolling after completion of the CNS-HYD201US trial. Titration days 
are only if needed to achieve a therapeutic dose of hydromorphone after which subjects will start on Day 1 of the trial. Optional titration days may be scheduled from 3 to 14 days apart depending 
on the investigator discretion.
d.
Day 1 of the trial is considered the first day of the long term extension period. All subjects should be titrated to a therapeutic dose prior to starting Day 1. Day 1 may include a dose adjustment as 
needed.


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e.
Informed consent for subjects entering the CNS-HYD202US trial after completion of the CNS-HYD201US trial may be obtained as early as 30 days prior to completion of the CNS-HYD201US 
trial.
f.
For subjects entering the CNS-HYD202US trial from the CNS-HYD201US trial, medical history will be carried over from the previous trial and does not need to be repeated.
g.
For subjects entering the CNS-HYD202US trial from the CNS-HYD201US trial, Physical Examination, will be completed on the final visit day of the CNS-HYD201US trial, which is Day -1 of 
the CNS-HYD202US trial.
h.
Pump refills will be conducted as necessary to adjust the treatment regimen and conduct pump refills. Pump refills are not required at all visits.
i.
Dose adjustments are allowed during the long-term follow up period both as an increase or decrease to optimize the dose. The maximum dose is 10 mg/day of hydromorphone hydrochloride.
j.
If there are clinical signs of a granuloma as defined in Section 3.3, the Medical Monitor should be notified and an MRI (with and without contrast) or CT myelogram scheduled to confirm the 
pathology of the granuloma.
k.
VASPI, COWS, BPI and PGIC are administered at the study site on specified visits.
l.
At the final study visit, the investigator will remove the residual study drug from the subjects pump and will replace the study drug with normal standard of care medication/therapy.


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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: Brief Pain Inventory (BPI)


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Appendix F: Patient Global Impression of Change (PGIC)



SAP_001.pdf: 
Protocol CNS-HYD202US 
 
 
 
 
 
Piramal Critical Care, Ltd. 
04 Feb 2019 
Page 1 of 31 
Version 4.0 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Title: 
A Phase 3, Open-Label, Single-Arm Study to Assess the Safety of 
Hydromorphone Hydrochloride Delivered by Intrathecal 
Administration 
Protocol: 
CNS-HYD202US 
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 4.0 
Status: 
 
Final 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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TABLE OF CONTENTS 
 
GLOSSARY OF TERMS .................................................................................................................... 5 
1 
Introduction ............................................................................................................................. 7 
2 
Purpose of the Analysis .......................................................................................................... 7 
3 
Study Objectives ..................................................................................................................... 8 
4 
Study Design ........................................................................................................................... 8 
5 
Data Management ................................................................................................................. 12 
6 
Definition of Populations ...................................................................................................... 12 
7 
Definition of Study Endpoints .............................................................................................. 12 
7.1 
Primary Safety Endpoints ..................................................................................................... 12 
7.2 
Secondary Endpoints ............................................................................................................ 13 
8 
Statistical Methods ................................................................................................................ 13 
8.1 
Sample Size .......................................................................................................................... 13 
8.2 
Randomization and Masking ................................................................................................ 13 
8.3 
Subject Discontinuation and Replacement of Subjects ........................................................ 13 
8.4 
Final Analysis and Reporting ............................................................................................... 14 
8.5 
Handling of Missing Data ..................................................................................................... 14 
8.6 
Interim Analysis .................................................................................................................... 15 
8.7 
Comments on Statistical Analysis ........................................................................................ 15 
9 
Statistical Analyses ............................................................................................................... 16 
9.1 
Subject Disposition ................................................................................................... 16 
9.2 
Screening and Baseline Characteristics .................................................................... 16 
9.2.1 
Demographics and Baseline characteristics .............................................................. 16 
9.2.2 
Complete Physical Examination ............................................................................... 16 
9.2.3 
Medical History ......................................................................................................... 16 
9.2.4 
Prior Concomitant Medications................................................................................. 17 
9.2.5 
Vital Signs and Electrocardiogram (ECG) ................................................................ 17 
9.2.6 
Clinical Laboratory Assessments .............................................................................. 17 


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9.3 
Study Drug Exposure, Admixtures and Compliance ................................................ 18 
9.4 
Protocol Deviations .................................................................................................. 18 
9.5 
Safety Analyses ........................................................................................................ 18 
9.5.1 
Adverse Events .......................................................................................................... 18 
9.5.2 
Granulomas ............................................................................................................... 19 
9.5.3 
Vital Signs and Weight .............................................................................................. 20 
9.5.4 
Physical Examinations .............................................................................................. 20 
9.6 
Secondary Endpoints ................................................................................................ 20 
9.6.1 
Visual Analogue Scale of Pain Intensity (VASPI) .................................................... 20 
9.6.2 
Brief Pain Inventory (BPI) ........................................................................................ 21 
9.6.3 
Patient Global Impression of Change (PGIC) ........................................................... 21 
9.7 
Clinical Opiate Withdrawal Scale (COWS) ............................................................. 21 
10 
Summary of Amendments to the SAP .................................................................................. 23 
Appendix A ........................................................................................................................................ 25 
Appendix B ........................................................................................................................................ 28 
 


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GLOSSARY OF TERMS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory 
BSA 
Body Surface Area 
COWS 
Clinical Opiate Withdrawal Scale 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
PTM 
Personal Therapy Manager 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
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 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be performed for 
the analysis of data from Protocol CNS-HYD202US, “A Phase 3, Open-Label, Single-Arm Study 
To Assess The Safety Of Hydromorphone Hydrochloride Delivered By Intrathecal Administration.” 
 
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.  The following documents were reviewed in preparation of this SAP: 
 
This SAP is an amended version of the original SAP for the CNS-HYD202US trial that was finalized 
on 06 August 2012 as Version 1.0 and amended as:  
 Version 1.1 on 26 September 2012, 
 Version 1.2 on 15 April 2013, 
 Version 2.0 on 28 August 2013, 
 Version 3.0 on 21 March 2014,  
 Version 4.0 on 16 September 2014,  
 Version 5.0 on 18 December 2014, 
 Version 6.0 on 24 June 2016, and  
 Version 7.0 on 01 August 2016. 
 
The following documents were reviewed in preparation of this SAP: 
 
 Final Clinical Protocol CNS-HYD202US, Version 7.0, issued 01 August 2016 
 
 Case report forms (CRFs) for Protocol CNS-HYD202US 
 
 
2 
Purpose of the Analysis 
 
The purpose of this SAP is to outline the planned analyses to be completed to support the Clinical 
Study Report (CSR) for Protocol CNS-HYD202US. 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 the original plans.  Piramal made a 
business decision to proceed with only certain analyses of the study. All subjects completed the 
study as planned and all data pertaining to the selected safety analyses were cleaned and queried 
through 08 January 2018, due to the decision to analyze only safety data.  Database lock occurred 
on 07 February 2018.  Subsequently, Piramal made the decision to go forward with the entire 
analysis of the study. No further cleaning of the data modules was performed.  This Amended SAP 
described the updates in the conduct and analysis of the trial due to these decisions.  


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3 
Study Objectives 
The purpose of this clinical study is to demonstrate the long term 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. 
 
Primary Objective 
 
To evaluate the long-term (12-month) safety of 2 mg/mL and 10 mg/mL hydromorphone 
hydrochloride given by the intrathecal route of administration. 
 
 
4 
Study Design 
 
This is an open-label, single-arm study to evaluate the safety of hydromorphone hydrochloride 
given by continuous intrathecal infusion using an implantable pump device. This clinical trial will 
be conducted at up to 30 clinical trial sites that are experienced with the use of intrathecal opioids.  
This study will enroll both subjects on a current opioid (e.g., morphine or hydromorphone 
hydrochloride) intrathecal medication as well as naïve subjects not currently on intrathecal opioid 
medications. Dosing regimens allowed in this study will include simple continuous, complex 
continuous and Personal Therapy Manager (PTM) dosing. 
 
For subjects entering the trial already on a therapeutic dose of hydromorphone hydrochloride, the 
hydromorphone hydrochloride will be replaced by the study drug (hydromorphone hydrochloride for 
intrathecal injection) on a 1:1 basis without dose adjustment or optional titration days. The subject is 
considered at a therapeutic dose and will start the study on Day 1. 
 
Subjects converted from an intrathecal opioid therapy other than hydromorphone hydrochloride to 
the study drug will be dosed with the study drug according to the following conversion scheme: 
 
Subject on Morphine or on another 
Opioid 3 
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. 
3 Convert the opioid to mg-morphine equivalent dose first. Then convert to hydromorphone hydrochloride based 
on mg-morphine equivalent dose using the conversion scheme. 
 
Subjects who are converted directly to the study drug based on the 1:6 morphine-equivalence ratio 
are, by definition, at a therapeutic dose and must start the study on Day 1 without titration. Dose 
adjustments may be performed at subsequent visits, based on the investigator discretion. 


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For subjects converted using 1:12 conversion ratio, due to safety considerations, the conversion will 
be followed by up to five (5) optional titration days (Titration Days A, B, C, D and E) to achieve a 
therapeutic dose before starting Day 1. These optional titration days may be three (3) to fourteen 
(14) days apart. 
 
In subjects receiving an intrathecal opioid in combination with another drug(s) prior to the 
enrollment of the study, the intrathecal opioid will be converted directly to the study medication (see 
the conversion scheme above) while the dose of the other drug(s) used in the combination should be 
kept the same. 
The conversion will take place by removing the current intrathecal opioid therapy in the pump and 
then replacing the contents with study hydromorphone hydrochloride for intrathecal injection. At the 
discretion of the investigator the pump reservoir may be rinsed with preservative free sterile saline or 
study medication (hydromorphone hydrochloride for intrathecal injection). 
 
Dose adjustments may occur for any subject during the study, either on scheduled or unscheduled 
visit after study Day 1, as needed 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 % 
 
As needed, additional intrathecal concomitant medications may be added to the therapy to optimize 
pain control. 
 
Subjects who are naïve to intrathecal analgesics will have the pumps filled initially with a 2 mg/mL 
hydromorphone hydrochloride for intrathecal injection. Naïve subjects will be initiated on a dose 
between 0.1 mg/day and 0.5 mg/day, based on their current opioid dose and the discretion of the 
investigator. These subjects will be allowed up to five (5) optional titration days to achieve a 
therapeutic dose of hydromorphone prior to starting the long term safety period on Day 1 of this 
study. These optional titration days may be three (3) to fourteen (14) days apart. It is suggested that 
prior to a dose adjustment above 1 mg/day, the pump should be drained and refilled with 10 mg/mL 
hydromorphone hydrochloride and pump speed adjusted to achieve the target dose. Dose 
adjustments may continue as needed to optimize the therapy. After achieving a therapeutic dose of 
hydromorphone hydrochloride, additional intrathecal concomitant medications may be added to the 
therapy to optimize pain control for these subjects. 
 
Subjects continuing on therapy from the CNS-HYD201US trial will remain at their current dose of 
hydromorphone hydrochloride and start at Day 1 of this study. Subjects who were titrated off of 
hydromorphone hydrochloride as part of the CNS-HYD201US control arm will be titrated back to a 
therapeutic dose using one or more optional titration days prior to Day 1 of this study. 
 
A maximum dose 10 mg/day intrathecal hydromorphone hydrochloride is permitted at any time 
during this study. For subjects on PTM dosing regimens, the maximum daily dose will include the 
combined continuous dose and the allowed maximum PTM dose. All subjects should be contacted 


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by telephone 24 hours after initiating study medication of hydromorphone hydrochloride. 
Subjects may be given FDA approved oral supplemental opioid medication and other FDA approved 
non-opioid medications to help manage pain during the 12 month treatment. 
 
Subjects will remain on therapy for a total of 12 months or until discontinuation from the study. 
During this continuous dosing period, dose adjustments (up or down) are permitted to manage pain 
or side effects provided the maximum 10 mg/day dose of hydromorphone hydrochloride is not 
exceeded. All medications administered must be recorded. At no time may a contraindicated 
treatment be administered in combination with hydromorphone hydrochloride. Subjects will be 
assessed for pain intensity using a VASPI instrument at each study visit. 
 
Subjects will be evaluated for side effects and clinical complications associated with the use of 
intrathecal hydromorphone hydrochloride. Signs and symptoms of a suspected granuloma will be 
monitored; examples of these include but are not limited to radicular pain and loss of drug efficacy. 
 
If there are clinical signs or symptoms identified which may indicate an inflammatory mass 
formation, an MRI (with and without contrast) or CT myelogram should be performed (with consent 
of the subject) to evaluate the potential presence of a granuloma as opposed to other catheter related 
problems that may result in reduced delivery or clinical symptoms. Events will be classified by 
duration and concentration of intrathecal hydrophone hydrochloride. Events that may be related to a 
granuloma will be classified as confirmed granuloma or suspected granuloma. 
 
Table 1 contains the study schedule of procedures. 
 
 


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Table 1: 
Schedule Study Procedures 
 
Study Procedure 
Visit Schedule 
Study Daya 
Screening 
Days -14 
to 1b 
Baseline 
Days -3 
to 1b 
Baseline for 
HYD201US 
Subjectsb 
Optional 
Titration 
Daysb,c 
Day 
1b,d 
Day 
28 
Day 
56 
Day 
80 
Day 
104 
Day 
160 
Day 
216 
Day 
286 
Final 
Study 
Visit 
Day 
365 
Signed Informed Consent 
Xe 
X 
Medical Historyf 
X 
* 
Compete physical examg 
X 
* 
X 
Vital signs and Weightg 
X 
X 
* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test g 
X 
X 
X 
X 
ECGg 
X 
X 
CBC, CMP, Urinalysisg 
X 
X 
Concomitant medication assessment 
X 
X 
* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hydromorphone Hydrochloride 
Pump Dose Adjustment and Refills h,I,l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Oral Opioid 
X       -----------------------------------------------------------------------------------------------------------------
Clinical evaluation for Granulomasj 
X 
* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VASPI Assessmentk 
X 
X 
* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COWS Assessmentk 
X 
* 
X 
X 
BPIk 
X 
* 
X 
X 
X 
X 
X 
PGICk 
X 
* 
X 
X 
X 
X 
X 
 
a. 
Study Day is based on Day 1 defined as the first day a subject achieves a therapeutic dose of hydromorphone therapy. There is no Day 0 in this trial. Optional titration days for subjects below therapeutic 
levels will not be counted towards the 365 day study period. All visit days are +/- 7 days during the long-term extension phase of the study. Additional unscheduled visits may be scheduled to make dose 
adjustments or prescribe oral medication to manage pain and withdrawal symptoms as deemed appropriate by the investigator. 
b. 
Screening period is 14 days. Screening, Baseline and/or Initiation of Dosing (i.e. Optional Titration Day or Day 1) visits may be combined. For subjects entering the CNS-HYD202US clinical trial that are 
transitioning from the CNS-HYD201US efficacy trial, these subjects will not be required to repeat Screening. For these subjects the last day of the CNS-HYD201US trial will be considered the first day 
(either optional titration day or Day 1) of the CNS-HYD202US trial. Baseline assessments will be completed as part of the final day (Day 119 or Treatment Failure day) and only additional activities or tests 
shown on the Schedule of Events (shown in table of events as “X”) for these subjects are required to enter the CNS-HYD202US trial. Tests that are done as part of the final visit of the CNS-       
HYD201US trial and will not be repeated in this study are shown in the table with a “*”. 
c. 
Optional titration days are intended for subjects requiring titration after switching from other opioids or control arm subjects enrolling after completion of the CNS-HYD201US trial. Titration days are only if 
needed to achieve a therapeutic dose of hydromorphone after which subjects will start on Day 1 of the trial. Optional titration days may be scheduled from 3 to 14 days apart depending on the investigator 
discretion. 
d. 
Day 1 of the trial is considered the first day of the long term extension period. All subjects should be titrated to a therapeutic dose prior to starting Day 1. Day 1 may include a dose adjustment as needed. 
e. 
Informed consent for subjects entering the CSN-HYD202US trial after completion of the CNS-HYD201US trial may be obtained as early as 30 days prior to completion of the CNS-HYD201US trial. 
f. 
For subjects entering the CNS-HYD202US trial from the CNS-HYD201US trial, medical history will be carried over from the previous trial and does not need to be repeated. 


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g. 
For subjects entering the CNS-HYD202US trial from the CNS-HYD201US trial, Physical Examination, will be completed on the final visit day of the CNS-HYD201US trial, which is Day -1 of the CNS- 
HYD202US trial. 
h. 
Pump refills will be conducted as necessary to adjust the treatment regimen and conduct pump refills. Pump refills are not required at all visits. 
i. 
Dose adjustments are allowed during the long-term follow up period both as an increase or decrease to optimize the dose.  The maximum dose is 10 mg/day of hydromorphone hydrochloride. 
j. 
If there are clinical signs of a granuloma as defined in in the protocol, the Medical Monitor should be notified and an MRI (with and without contrast) or CT myelogram scheduled to confirm the pathology 
of the granuloma. 
k. 
VASPI, COWS, BPI and PGIC are administered at the study site on specified visits. 
l. 
At the final study visit, the investigator will remove the residual study drug from the subjects pump and will replace the study drug with normal standard of care medication/therapy. 


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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. All eCRFs 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 
eCRFs. Clinical monitors will also ensure that all protocol requirements, applicable FDA 
regulations, other requirements, and Investigator’s obligations are being fulfilled. 
 
Refer to the Data Management Plan for further details. 
 
 
6 
Definition of Populations 
 
The Safety Population includes all subjects who receive any study medication (i.e. 
hydromorphone hydrochloride intrathecal treatment). All summaries of safety data will be 
carried out using the safety population.  The Intent-to-Treat (ITT) Population also includes 
all subjects who receive any study medication.  The analysis of the secondary endpoints will 
be carried out on the ITT Population.   Inclusion in the Safety and ITT Populations will be 
determined programmatically from the eCRF 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.  It was determined that all 
data from this site will be included in the analysis of safety, but should not be included in the 
analysis of the secondary endpoints. Since this was taken mid-way through the study, the 
analysis of BPI, VASPI and PGIC will be performed on two populations: ITT Population 
Excluding Site 028 and on the ITT Population. Documentation of the site closure can be 
found in Appendix B. 
 
 
7 
Definition of Study Endpoints 
7.1 
Primary Safety Endpoints 
 


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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: 
 
 The rate of confirmed granulomas verified by MRI (with and without contrast), CT 
myelogram or by surgery. 
 The rate of suspected granulomas that cannot be verified by MRI (with and without 
contrast), CT myelogram or surgery. 
 
 
 
7.2 
Secondary Endpoints 
 
The following Secondary Endpoints will be assessed.  Each of these endpoints will be evaluated 
at each study visit. 
 
 Change in the Visual Analog Scale Pain Intensity (VASPI) overtime. 
 Change in the Brief Pain Inventory (BPI) overtime. 
 Change in the Patient Global Impression of Change (PGIC) overtime. 
 
 
 
8 
Statistical Methods 
8.1 
Sample Size 
 
This study is planned to enroll approximately 350 subjects at up to thirty (30) investigative sites 
to obtain 300 subjects completing 6-months and 100 subjects completing 12-months of 
intrathecal hydromorphone hydrochloride therapy. Additional subjects may be enrolled as 
deemed necessary to reach the study submission objectives for subjects on long term intrathecal 
hydromorphone hydrochloride therapy. 
 
8.2 
Randomization and Masking 
 
This is an open-label, single-arm safety trial.  As such there is no blinding. There is no 
randomization in this trial. 
 
Each subject who is entered from the CNS-HYD201US study will retain their subject number 
from the previous study and carry that number into this trial. 
 
Unique subjects enrolled directly into the CNS-HYD202US trial will be assigned a subject 
number consisting of a two-digit site number and three-digit sequential subject number (SS- 
XXX). This number will be used for the entire duration of the trial. 
 
8.3 
Subject Discontinuation and Replacement of Subjects 
 


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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. 
 
Additional subjects may be enrolled as deemed necessary to reach the study submission 
objectives of 300 subjects completing 6 months and 100 subjects completing 12 months of 
intrathecal hydromorphone hydrochloride therapy. 
 
 
8.4 
Final Analysis and Reporting 
 
Study submission objectives will be met when 300 subjects complete 6 months and 100 subjects 
complete 12 months of intrathecal hydromorphone therapy.  For the purpose of the clinical study 
report, the analyses may occur any time after the study submission objectives are met.  At the 
time of submission, some subjects may still be receiving study treatment.  Therefore, any 
subsequent safety data collected on those subjects will be submitted via a safety update, unless 
other format is requested by Regulatory Authorities.  Database lock will occur when all study 
submission objectives are met or subjects have completed the study (or discontinued early) and 
all data have been monitored. A business decision was made by Piramal to only perform the 
safety analysis of the study once all subjects had completed the study.  Modules pertaining to the 
safety data were monitored, cleaned and queried, while modules pertaining to the efficacy 
endpoints (VASPI, BPI, PGIC) data were no longer cleaned or queried after 11 September 2017.  
The database was locked on 07 February 2018.  Subsequently, Piramal made the business 
decision to move forward with the program and to complete the remaining analysis of the study.  
The remaining analyses will be performed under this version, Version 4.0 dated 04 February 
2019 of the SAP, and will be performed on the previously locked data.  No additional data 
cleaning will take place.   
 
In addition, no database may be locked, or final analyses completed until the original version of 
the SAP had 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; 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 
All missing data will remain missing and will not be imputed. Only observed data will be 


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summarized.  The only exception is in the BPI total score as described in the corresponding 
section. 
 
8.6 
Interim Analysis 
 
No formal interim analyses will be conducted. See section 8.4 of the SAP for further details 
regarding the timing of the analyses for study submission and the reporting of subsequent safety 
data. 
 
 
8.7 
Comments on Statistical Analysis 
 
The following general comments apply to all statistical analyses and data presentations: 
 
 Unless otherwise noted, tables will present summaries by formulation concentration (2 
mg/mL and 10 mg/mL) and all subjects. 
 
 Summaries will include frequency and percentages for categorical data and frequency, 
mean, standard deviation, median, minimum, and maximum for quantitative data. 
 
 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. Unless 
otherwise noted, all percentages will be presented to one decimal place. 
 
 
 


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9 
Statistical Analyses 
 
9.1 
Subject Disposition 
 
The number and percent of subjects in the Safety population will be summarized. The number 
and percent of subjects who enrolled in the study, completed the study, withdrew from the study 
and their reasons for withdrawal will also be tabulated. The number and percentage of subjects 
who rolled over from study CNS-HYD201US, subjects who were naïve to intrathecal opioids, 
and those who had prior opioid treatment will also be summarized.  Subject disposition will be 
summarized using all enrolled subjects. Enrolled subjects will be those subjects who signed the 
informed consent form. 
 
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 variables. 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 rounded down.  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 Complete Physical Examination 
 
The Investigator or designee will perform a complete physical examination at screening. Results 
will be recorded as part of the Medical History. Assessments of height, weight, calculation of 
BMI, 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. 
 
9.2.3 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 


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by system organ class and preferred term. Medical history verbatim terms and coded terms will 
be listed. 
 
Listings will also be provided with the following information: 
 
 History of intractable pain 
 
 Implantation of intrathecal pump and prior opioid use prior to pump implantation 
 
 Surgical intervention(s) for treatment of intractable pain 
 
9.2.4 Prior 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.  Medications are also considered concomitant if their 
stop date is unknown or marked as continuing.  Medications 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 and preferred term. 
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 prior and concomitant medications will also be prepared. 
 
9.2.5 Vital Signs and Electrocardiogram (ECG) 
 
Systolic and diastolic blood pressure, radial pulse, breathing rate and temperature will be 
obtained at baseline and each study visit and recorded. All vital signs will be obtained in a semi- 
recumbent position. 
 
A safety electrocardiogram (ECG) will be recorded at Screening or at Baseline for subjects 
previously enrolled in study in study CNS-HYD201US.  The ECG will be used to assess any 
cardiovascular abnormalities for the purposes of determining eligibility for this trial. 
 
The number and percentage of subjects with normal, abnormal not clinically significant and 
abnormal clinically significant ECGs will be summarized. ECG results will also be listed. 
 
9.2.6 Clinical Laboratory Assessments 
 


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Blood for chemistry, hematology, and urinalysis laboratory tests will be collected at Screening or 
Baseline for patients previously enrolled in study CNS-HYD201US. 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 will be listed. 
 
Serum pregnancy tests will also be conducted at Screening, Baseline and the Final Visit for 
women of childbearing potential.  Pregnancy test results will be listed 
 
9.3 
Study Drug Exposure, Admixtures and Compliance 
 
Dose adjustments and pump refills will be recorded and data listed for each subject.  Any 
admixtures (combination drugs) included into the hydromorphone hydrochloride will be 
recorded by combination type and dose of each component of the product in the pump and listed 
for each subject. 
 
 
9.4 
Protocol Deviations 
 
Deviations 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 
 
A listing of major protocol deviations that impact the evaluation of safety will be provided. 
 
9.5 
Safety Analyses 
 
Safety will be assessed using the Safety population. 
 
9.5.1 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 


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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. 
 
9.5.2 Granulomas 
 
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 CT scan 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. 
 
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 inflammatory 
granuloma, as well as, the incidence and rate of confirmed granuloma will be summarized by 
study drug concentration and all subjects. 
 
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 


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 Subjects with confirmed granuloma by MRI/CT via independent radiologist 
 
 
 
9.5.3 Vital Signs and Weight 
 
Systolic and diastolic blood pressure (mmHg), radial pulse (beats/minute), respiratory rate 
(breaths/minute), weight (kg), and temperature (°C) will be obtained at baseline and each study 
visit and recorded on the eCRF. 
 
All vital signs and weight measurements as well as change from Baseline for these 
measurements will be summarized 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.  A listing of subjects with potentially clinically significant vital signs 
will also be presented.  Table contains the criteria for identifying potentially clinically significant 
vital sign values. 
 
Table 2: 
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 
 
9.5.4 Physical Examinations 
 
The Investigator or designee will perform a complete physical examination at screening and at 
the final visit. The number and percentage of normal and abnormal physical exams will be 
summarized by body system at screening and at the final visit. Any clinically significant 
physical examination findings will be reported and analyzed as AEs or SAEs.  Physical 
examination findings will also be listed. 
 
9.6 
Secondary Endpoints 
 
9.6.1 Visual Analogue Scale of Pain Intensity (VASPI) 
 
The VASPI will be a single question assessing how severe a subject’s pain is ‘right now’. 


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Scoring is based on the continuous visual analog scale (measured in mm) ranging from no pain at 
the start of the scale to unbearable pain at the end of the scale. VASPI will be assessed at 
Baseline and each study visit, including the final visit. The VASPI scores, as well as change 
from baseline, will be summarized at each visit. All assessments will be listed. 
 
9.6.2 Brief Pain Inventory (BPI) 
 
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. 
 
The BPI will be assessed at Baseline, Day 28, Day 80, Day 160, Day 286, and at the final visit. 
The BPI scores, as well as change from baseline, will be summarized at each specified visit for 
the following: pain severity ‘worst’, pain severity ‘average’, calculated mean pain severity, and 
calculated mean pain interference with function. All assessment, including the calculated mean 
scores, will be listed. 
 
9.6.3 Patient Global Impression of Change (PGIC) 
 
The PGIC will be a single question that rates the overall change, if any, from Baseline in activity 
limitations, symptoms, emotions, and overall quality of life related to the subject’s painful 
condition based on a 7-point Likert scale from 1 (no change) to 7 (a great deal better). 
 
The PGIC will be assessed at Baseline, Day 28, Day 80, Day 160, Day 286, and at the final visit. 
The PGIC score will be summarized at each specified visit. All assessment will be listed. 
 
9.7 
Clinical Opiate Withdrawal Scale (COWS) 
 
The Clinical Opiate Withdrawal Scale (COWS) assessment will assess the severity of 11 opiate 
withdraw 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 assessment will be performed at 
Baseline and the final visit to evaluate any opiate withdrawal symptoms. The COWs total scores 


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will be summarized at each visit and the changes from baseline to the final visit will also be 
summarized.  Individual item scores and the total score for the COWS 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 
 Changed sponsor information (MNK acquired CNS Therapeutics). 
 Text for study objectives, endpoints, study design, and schedule of events all 
updated to match protocol amendment 4.0 dated 16Sep2014 which 1] clarified 
aspects of the study design that were unclear due to the complicated nature of 
the study, particularly with regard to conversion from morphine to study drug 
and 2] better organized the flow of text throughout, including language with 
regard to endpoints – see protocol amendment change summary for individual 
details). 
 Added clarification that submission objectives would be met when 300 subjects 
had 6 months of exposure and 150 subjects had 12 months of exposure (reflect 
protocol amendment 4.0 dated 16Sep2014). 
 Rewrote text regarding analyses of AEs (improve section flow and better 
describe the analyses themselves). 
 Updated text for evaluation of granulomas to match protocol amendment 4.0 
dated 16Sep2014 and clarified that analyses would be performed for both 
possible and confirmed granulomas, as well as, added text describing the 
evaluation of granuloma signs and symptoms (reflect protocol amendment 4.0 
dated 16Sep2014). 
 Include definitions for clinically significant vital sign changes for systolic/diastolic 
blood pressure and weight (added for clarification). 
3.0 
 Typos corrected (clean up of document) 
 Clarified timing of main objective is at 12-months exposure for the 2mg/mL and 
10mg/mL concentrations (based on protocol amendment 5 dated 18Dec2014). 
 Updated medical history text to describe the coding of terms (clarification). 
 Removed text that indicated latest version of MedDRA would be used for AE 
coding (dictionary version should remain stable to avoid constant recoding 
through long duration of study. 
 Changed protocol deviation to protocol violation (to match MNK standards). 


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 Consolidated and moved description of BPI, PGIC, and VASPI into a secondary 
endpoints section (improve flow). 
 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). 
 Added some description details to the PGIC, VASPI, and COWs (provided basic 
details on how the assessments were structured but made no changes to the 
original analyses). 
 Added Summary of Amendments to the SAP section (provide historical 
reference). 
4.0 
 Described the timeline of safety and efficacy analyses for the study 
 Described the exclusion of subjects from Site 028 
 Clarified the analysis populations 
 Added Appendix A – list of Tables and Listings for output 
 Added Appendix B  - documentation of Site 028 closure 
 Corrected version dates of protocol and amendments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A 
 
The following Tables and Listings 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. 
 
 
Tables 
 
 Number 
Title 
Analysis 
Population 
14.1.1 
Subject Disposition 
Safety 
14.1.2 
Demographics and Baseline Characteristics 
Safety 
14.1.3 
Medical History 
Safety 
14.1.4.1 
Prior Medications 
Safety 
14.1.4.2 
Concomitant Medications 
Safety 
14.1.5 
12-Lead Electrocardiogram 
Safety 
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 
Overview of Adverse Events   
Safety 
14.3.1.2 
Incidence of Adverse Events by System Organ Class 
and Preferred Term   
Safety 


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14.3.1.3 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term   
Safety 
14.3.1.4 
Incidence of Adverse Events by System Organ Class, 
Preferred Term and Severity to Study Drug   
Safety 
14.3.1.5 
Incidence of Serious Adverse Events by System 
Organ Class and Preferred Term and Severity to 
Study Drug   
Safety 
14.3.1.6 
Incidence of Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug   
Safety 
14.3.1.7 
Incidence of Serious Adverse Events by System 
Organ Class, Preferred Term, and Relationship to 
Study Drug   
Safety 
14.3.5.1 
Vital Signs  - Open Label Phase 
Safety 
14.3.5.2 
Potentially Clinically Significant Vital Signs   
Safety 
14.3.5.3 
Physical Examination Findings by Body System   
Safety 
14.3.5.4 
Granuloma Assessment 
All Enrolled Subjects 
14.3.5.5.1 
14.3.5.5.1Visual Analog Scale of Pain Intensity 
(VASPI) 
ITT 
14.3.5.5.2 
Visual Analog Scale of Pain Intensity (VASPI) 
ITT Excluding Site 028 
14.3.5.6.1.1 
Brief Pain Inventory - Pain Severity Measures 
ITT 
14.3.5.6.1.2 
Brief Pain Inventory - Pain Severity Measures 
ITT Excluding Site 028 
14.3.5.6.2.1 
Brief Pain Inventory  - Pain Interference 
ITT 
14.3.5.6.2.2 
Brief Pain Inventory  - Pain Interference 
ITT Excluding Site 028 
14.3.5.7.1 
Patient Global Impression of Change (PGIC) 
ITT 
14.3.5.7.2 
Patient Global Impression of Change (PGIC) 
ITT Excluding Site 028 
14.3.5.8 
Clinical Opiate Withdrawal Scale (COWS) 
Assessment 
ITT 
14.3.6 
Study Drug Exposure Summary   
Safety  
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 
Adverse Events 
All Enrolled Subjects 
16.2.7.2 
Serious Adverse Events 
All Enrolled Subjects 


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16.2.7.3 
Adverse Events Leading to Discontinuation 
All Enrolled Subjects 
16.2.7.4 
Adverse Events Leading to Death 
All Enrolled Subjects 
16.2.8 
Oral Opioid Supplements 
All Enrolled Subjects 
16.2.9 
Vital Signs 
All Enrolled Subjects 
16.2.10 
Physical Examination Assessments 
All Enrolled Subjects 
16.2.11.1 
Clinical Evaluation of Inflammatory Mass Formation 
All Enrolled Subjects 
16.2.11.2 
Signs or Symptoms of Granuloma 
All Enrolled Subjects 
16.2.11.3 
MRI and CT Myelogram 
All Enrolled Subjects 
16.2.11.4 
Central Reader for MRI and CT Myelogram 
All Enrolled Subjects 
16.2.12.1 
Visual Analog Scale of Pain Intensity (VASPI) 
All Enrolled Subjects 
16.2.12.2 
Brief Pain Inventory (BPI) 
All Enrolled Subjects 
16.2.12.3 
Patients' Global Impression of Change (PGIC) 
All Enrolled Subjects 
16.2.13 
Clinical Opiate Withdrawal Scale (COWS) 
All Enrolled Subjects 
16.2.14.1 
Exposure Summary - Dose Data 
All Enrolled Subjects 
16.2.14.2 
Exposure Summary - Pump Information 
All Enrolled Subjects 
16.2.14.3 
Exposure Summary – Dose Interruption 
All Enrolled Subjects 
16.2.14.4 
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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