Conditions: Cancer Cachexia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of repeated oral administration of macimorelin at different doses daily for 1 week for the treatment of cancer cachexia.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Macimorelin intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will receive macimorelin (1 mg/kg) and matching placebo (Powerade®) daily for 7 days. intervention 2: placebo (Powerade®) daily for 7 days.

Protocol document:
Prot_SAP_000.pdf: 
Human Subjects Protocol
VA Puget Sound IRB
Pilot clinical trial of Macimorelin to assess safety and efficacy in patients with Cancer
Cachexia
MIRB #00954
Funding Agency: VAISIBCR
Principal Investigator: Jose Garcia
02/06/2018
VA Puget Sound IRB Approved
03/05/20 18


Abstract
Every year, over 1.5 million individuals in the US are diagnosed with cancer. Cachexia,
defined as an involuntary weight loss >5%, and anorexia (decreased food intake and appetite)
are present in up to 80% of these patients, decreasing functional performance, quality of life
(QOL) and survival. However, treatments for this condition are lacking. Feeding behavior is
maintained by a network of interconnected brain areas, including the hypothalamus and striatum.
The striatum signals the rewarding effects of food, while the hypothalamus responds to states
such as hunger and satiety. The extent to which cancer cachexia and anorexia affect these
circuits and their response to different interventions have not been characterized. In non-cancer
models, administration of ghrelin or its mimetics decreases resting energy expenditure (EE) and
inflammation and increases food intake and food reward. This leads to an increase in lean body
mass (LBM) and fat mass. However, its role in cancer anorexia-cachexia syndrome (CACS) is
not well-characterized. To study the pathways regulating appetite
in this setting and the
mechanisms mediating the effects of ghrelin mimetics on food intake and reward, we will perform
functional Magnetic Resonance Imaging studies on cancer patients with cachexia before and
after receiving the ghrelin mimetic macimorelin for 7 days. There are no published reports
studying the different components of CACS in the human brain. We will assess its effects on
hypothalamic and reward centers in the brain, and the effects of macimorelin on brain activity
related to food intake.
Hypothesis: in CACS, compared to placebo, macimorelin will: a) increase appetite, food intake,
and food reward, b) decrease REE and inflammation, c) improve QOL.
Specific aim: to determine the role of macimorelin on appetite, food intake, energy expenditure,
inflammation, food reward, and QOL in CACS.
In this double-blind, placebo-controlled trial,
subjects with CACS will be randomized to placebo (N=2) v. macimorelin (N=6). Comparisons will
be made between groups for changes from baseline in appetite (visual analogue scale), food
intake (food diary and test meal), body weight, serum cytokines, REE (indirect calorimetry), food
reward (fMRI), and QOL (questionnaires).
Significance: There is currently no effective therapy for CACS. This study will increase our
understanding of the brain mechanisms mediating CACS, a necessary step in the development
of effective therapies. These results are expected to open new avenues for treating symptoms
associated with cancer and to improve QOL in this population. The present proposal will: a)
Establish for the first time the extent to which abnormalities in food reward contribute to CACS in
humans; b) Validate the use of fMRI in the study of cancer-related appetite regulation in humans
which until now relies heavily in rodent data; and c) Establish the role of macimorelin in this
setting and provide insight into its mechanisms of action by establishing the relative contribution
of changes in food intake, food reward, and REE.
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List of Abbreviations
AEZS
?Eterna Zentaris
ALT
Alanine transaminase (SGPT)
ASAS
Anderson Symptom Assessment Scale
AST
Aspartate transaminase (SGOT)
BIA
Bioimpedance Analysis
BMI
Bodymassindex
BUN
Blood urea nitrogen
CBC
Complete blood count
CFR
Code of Federal Regulations
CMP
Comprehensive Metabolic Panel
C02
Carbon dioxide
CRP
C-Reactive Protein
CPRS
Computerized Patient Record System
CTCAE
Common Terminology Criteria for Adverse Events
DLDCC
Dan L. Duncan Cancer Center
DXA
Dual Energy X-Ray Absorptiometry
DMC
Data Monitoring Committee
DTI
Diffusion Tensor Imaging
ECOG PS
Eastern Cooperative Oncology Group Performance Status
ECG
Electrocardiogram
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
Food and Drug Administration
FSH
-
Follicle-Stimulating Hormone
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fMRI
Functional Magnetic Resonance Imaging
GCP
Good Clinical Practices
GH
Growth Hormone
GHS-R
Growth Hormone Secretagogue Receptor
HbA10
Hemoglobin A1
hCG
Human Chorionic Gonadotropin
HGS
Handgrip strength
HIPAA
Health Information Portability and Accountability Act
HIV
Human immunodeficiency virus
hs-CRP
High sensitivity CRP
H&P
History and Physical
ICH
International Conference on Harmonization
IGF-l
Insulin-like growth factor-i
IGFBP-3
Insulin-like growth factor binding protein-3
lL-6
Interleukin-6
IRB
Institutional Review Board
ITT
Intent to treat
MedDRA
Medical Dictionary for Regulatory Activities
NSCLC
Non-small cell lung cancer
NCI
National Cancer Institute
REE
Resting Energy Expenditure
RSFC
Resting State Functional Connectivity
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SCP
Stair Climbing Power
USA
United States of America
VAS
Visual Analogue Scale
VCO2
maximal Carbon dioxide
V02
maximal oxygen uptake
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Contents
1.0
Study Personnel
.7
2.0
Introduction
8
2.1
Synopsis
8
2.2
Overview of Target Condition: Cancer Cachexia
13
2.3
Anorexia and its contribution to cancer-cachexia
14
2.4
Ghrelin and Food Reward
14
2.5
Safety of Ghrelin in the Setting of Cancer
14
2.6
Rationale for Macimorelin Administration in Cancer Cachexia
15
2.7
Summary of Clinical Experience with Macimorelin
16
3.0
Objectives
17
3.1
Primary Objective
17
3.2
Secondary Objectives
17
3.3
Safety Objectives
18
4.0
Resourcesand Personnel
18
5.0
Study Procedures
18
5.1
Study Design
18
5.2
Study Drug
19
5.3
Blinding
20
5.4
Drug Inventory and Disposition
20
5.5
Screening Visit
20
5.6
Day 1 Visit
22
5.7
Day 7 Visit
23
5.8
Post-Study Visit
24
5.9
Recruitment Methods
25
5.10 Informed Consent Procedure
25
5.11 Inclusion/Exclusion Criteria
26
5.12 Study Evaluations
28
6.0
Reporting
34
7.0
Privacy and Confidentiality
37
8.0
Information Security and Data Storage/Movement
37
9.0
References
38
Appendix I: NCI-CTCAE, version 4
43
Appendix II: Drugs That Prolong the QT Interval
42
Appendix Ill: Drugs That Induce CYP3A4
45
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Protocol Title: Pilot clinical trial of Macimorelin to assess safety and efficacy in
patients with Cancer Cachexia
1.0
Study Personnel
Principal Investigator:
Jose Garcia M.D., Ph.D.
Associate Professor, Department of Medicine
Division of Gerontology & Geriatric Medicine
University of Washington School of Medicine
Clinician Investigator
Geriatric Research, Education and Clinical Center
VA Puget Sound Health Care System
Building 1, Room 815J
1660 South Columbian Way (S-182-GRECC)
Seattle, WA 98108-1597
Jg77uw.edu
Phone: (206) 764-2984
Fax: (206) 764-2569
Co-Investigators:
Daniel Wu, M.D., Ph.D.
Associate Professor, Department of Medicine
Associate Director, Hematopathology, University of Washington
VA Puget Sound Health Care System
- Seattle Division
1660 S. Columbian Way
Seattle, WA 981 08-1 597
Ellen Schur, M.D., MS.
Associate Professor, Department of Medicine
Division of General Internal Medicine
University of Washington
Harborview Medical Center
325 Ninth Ave
Box 359780
Seattle, WA 98104
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2.0
Introduction
2.1
Synopsis
This study is a continuation of a sequential protocol initiated at the Houston VA wherein
safety and assessment of a daily, weeklong administration of an initial Macimorelin dose
was assessed before proceeding with additional assessment of various doses. The
following flow chart summarizes that study design:
Group 1: macimorelin 0.5 mg/kg qd (n=6), vs.
placebo (n=4) for 7 days
Safety and Efficacy assessment
7z
Safety and efficacy of the Group 1 dose was completed while still an active protocol in
Houston. It was determined that there were no safety issues but there was inadequate
efficacy (defined as a 0.8 kg of body weight gain or a 50 ng/mL increase in plasma
IGF-1 levels or an improvement in quality of life questionnaires of at least 15% compared
to placebo). The protocol continued with Group 2 recruitment only. One patient completed
the Group protocol before the study was moved with Dr. Garcia to the Puget Sound VA.
Herein we submit the detailed protocol for continuation with Group 2 only. Note: placebo
patients from Groups I (N=4) and 2 (N=2) will be combined for comparison to the
Macimorelin group(s). A synopsis of the protocol is provided below.
Title
Pilot clinical trial of Macimorelin to assess safety and efficacy in
patients with cancer cachexia
Principal
Investigator!
Jose M. Garcia, MD, PhD
Investigational
VA Puget Sound Health Care System
Site/Sponsor
Building 1, Room 815J
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No safety issues
No safety issues
Minor safety issues
Inadequate efficacy
Adequate efficacy
Adequate efficacy
Group 2: macimorelin 1 mg/kg
qd (n=6), vs. Placebo (n=2) for
7 days
Group 3: macimorelin 0.25
mg/kg qd (n=6), vs. Placebo
(n=2) for 7 days
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1660 South Columbian Way (S-182-GRECC)
Seattle, WA 98108-1597
Jg77uw.edu
Phone: (206) 764-2984
Fax: (206) 764-2569
Drug source/Medical
Drug source:
Monitor
/Eterna Zentaris, Inc
50 Weismullerstrasse
Frankfurt
60314
Germany
Medical Monitor:
Jose M. Garcia, MD, PhD
VA Puget Sound Health Care System
Building 1, Room 815J
1660 South Columbian Way (S-182-GRECC)
Seattle, WA 98108-1597
Jg77@uw.edu
Phone: (206) 764-2984
________________________
Fax: (206) 764-2569
Study Duration
November 2016-November 2017 (estimated)
Study Objectives
Primary Obiectives:
To
evaluate
the
safety
and
efficacy
of oral
administration
of
macimorelin daily for
I week
in view of a development for the
treatment of cachexia based using the following parameters:
1.
Change of body weight (kg) between day 1 and day 7
2.
Change of plasma IGF-1 between day 1 (prior to dose) and day 7
3.
Change of quality of life score (ASAS, FACIT-F) between day 1
and day 7
Secondary Objectives:
1. Food intake as measured by a food diary to be recorded for 3 days
before days
1 and 7 and by a test meal done at screening and on
day 7.
2. Change of appetite measured by a validated visual analogue scale
(VAS) between day 1 and day 7.
3. Body composition as measured by bio-impedance (BIA) and dual
energy x-ray absorptiometry (DXA) on days I and 7.
4. Muscle strength as measured by handgrip strength (HGS) and
stair climbing power (SCP).
5.
Resting energy expenditure (REE) as measured
by
indirect
calorimetry.
_____________________
6. Change in IGFBP-3, GH, CRP, IL-6, TNF-a, and glucose between
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day I and day 7.
7. Changes in reward from food as measured by brain functional
Magnetic Resonance Imaging (fMRl).
8. Changes in functional brain connectivity as assessed by Resting
State Functional Connectivity (RSFC) imaging and Diffusion Tensor
Imaging (DTI).
Safety Obiectives:
1.
Clinical laboratory parameters:
complete blood count (CBC),
comprehensive metabolic panel (CMP), urinalysis (UA)
2. Vital signs,
3. Electrocardiogram (ECG) at days 1 and 7 before and 1 hour after
dosing and on the post-study visit.
4. Recording of adverse events from day I to day 7
Long-Term Obiective:
The long-term objective of this research is to determine the extent to
which the ghrelin mimetic macimorelin will affect energy intake and
energy expenditure, and the effect that these changes will have on
body weight, body composition, and functional performance in cancer
patients with cachexia
Population
Approximately 8 patients with diagnosis of cancer induced cachexia
(defined as a weight loss of 5% body weight in the 6 months prior to
screening) will be randomized 3:1 to macimorelin vs. placebo.
Design
In
this
double-blind,
placebo-controlled
trial,
patients
will
be
randomized to: 1) placebo or 2) macimorelin given daily for I week.
Safety and efficacy will be assessed at 1 week. Comparisons will be
made for changes from baseline between groups.
Relevance
The present proposal will improve our understanding of symptoms
that affect cancer patients. Collectively, these outcomes will establish
the role of ghrelin mimetics in cancer cachexia and give us an insight
into their mechanisms of action. This will improve quality of life and
may open new avenues for the treatment of these symptoms. An
improvement in functional performance is expected to allow patients
to stay home longer, decreasing the need for hospitalizations and
reducing the cost of healthcare.
Treatments
Patients will receive macimorelin (1mg/kg) or placebo (Powerade®)
daily according to the protocol as stated in the ‘study design’ section.
Inclusion/Exclusion
Inclusion:
1. Patients 1 8 years of age with histological diagnosis of active solid
or hematological malignancies
2. ECOG performance status of 0-2,
3. Presence of cancer-related cachexia defined as an involuntary
weight loss of at least 5% of the pre-illness body weight over the
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previous 6 months, and
4. Provide written informed consent prior to screening.
Exclusion:
1. Obesity (body weight >140 Kg);
2. Recent active excessive alcohol or illicit drug use;
3. Severe depression as determined by the investigator;
4. Other causes of cachexia such as: Liver disease (AST or ALT> 3x
normal levels); renal failure (creatinine >1.5 mg/dL), untreated thyroid
disease, class lll-IV CHF, AIDS, severe COPD requiring home 02;
5. Inability to increase food intake (e.g., esophageal obstruction,
intractable nausea and vomiting);
6.
Any condition that would prevent the patient from performing the
research procedures (e.g. unstable coronary artery disease);
7. Use of growth hormone, megestrol, Marinol, or any other anabolic
agents, appetite stimulants, tube feeding, or parenteral nutrition
during the 1 month prior to entering the study.
8. Systemic corticosteroids administration for> 6 days a month (i.e.
daily continuous schedule).
9.
Recent administration (less than
1 week) of highly emetogenic
chemotherapy (Hesketh scale class 4-5); patients may otherwise be
undergoing chemotherapy.
10. Being female and pregnant, breast-feeding or of childbearing
potential. (Note: Lack of childbearing potential for female patients is
satisfied by: a) being post-menopausal; b) being surgically sterile; c)
practicing contraception with
an
oral contraceptive,
intra-uterine
device, diaphragm, or condom with spermicide for the duration of the
study; or d) being sexually inactive. Confirmation that the patient is
not pregnant will be established by a negative urine hCG pregnancy
test at the time of enrollment.
11. Co-administration of drugs that prolong QT interval (Appendix II),
CYP3A4 inducers (Appendix Ill), QTc equal to greater than 450ms at
screening or other investigational agents (a wash-out period of five
times the half-life of drugs that prolong QT will be allowed with
approval of prescriber).
12.
Conditions that would
preclude
from successfully scanning
patients in MRI:
a. Claustrophobia (this would make lying in the scanner very
uncomfortable); b. having a pacemaker, aneurysm clips,
neurostimulators, cochlear implants, metal in eyes, steel worker, or
other implants; c. History of Seizures, d. History of head injuries
_________________________
resulting in loss of consciousness > 10 minutes.
Statistics
This is a pilot and exploratory study to assess safety and efficacy.
_________________________
The data generated through this trial will be used to power a future,
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larger clinical trial.
All efficacy variables will be summarized descriptively by treatment
using N, mean, SEM, and standard deviation. Data from placebo-
receiving patients from all groups will be pooled together for the
purpose of analyses since their treatment will be identical. Analyses
will
be done as changes from baseline using paired t-test for
continuous variables and Fisher’s exact test for categorical variables.
Also, one-way ANOVA will be used to compare the differences in
outcomes
between
groups.
Appropriate
transformations
will
be
applied to the outcome changes to improve distribution toward
normality. As recommended by the CONSORT guidelines (1), we will
develop both completers and intention-to-treat models.
We have selected primary endpoints for each specific aim based on
the clinical relevance of each outcome and the research questions
proposed. Other endpoints will be considered secondary endpoints
that will provide supplemental evidence to the conclusions drawn
from these primary variables or will explore different areas.
Full
disclosure and complete description of all endpoints will be included
in
public presentations of data to avoid bias. Safety,
including
adverse events, ECGs, vital signs, and laboratory assessments will
be summarized descriptively by treatment group.
Analysis of fMRI data will be as follows: We use a general linear
model in analyzing and designing our fMRI experiments. To compare
data from different patients, the scan data from each patient must be
transformed into a standard anatomical framework. We follow the
approach of Frackowiak et al (1997), which analyzes the brain into
small local volumes, or “voxels.” The fMRI signal from each voxel is
then subjected to the following transformation and analysis steps:
Analysis Step 1: Spatio-temporal normalization to a standard brain
map, and smoothing to improve the signal to noise ratio.
Analysis Step 2: Statistical analysis to determine the significance of
the activity measured at each voxel. We use an established statistical
framework (2, 3) in terms of a general linear model, which
incorporates and formalizes the independent explanatory variables in
our experiment.
Given the variance of each parameter, we can construct a t-statistic
as a measure of the significance of differences in the parameters
estimated from different experiments, at different voxels, or in
different patients. In practice, we construct a t-statistic out of a
_________________________
particular linear combination of the parameters that describes a
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quantity of interest. To express this mathematically, we define a
contrast vector that specifies a linear combination of parameters.
Then the t-statistic is the quantity of interest divided by its standard
error. When we calculate a t-statistic at each voxel in an imaged
brain, measuring the significance of a difference between parameters
from different patients or different experimental conditions, the
resulting set is called a statistical parametric map. We use such
maps to determine areas of significant activation in the brain during
presentation of stimuli or performance of the task. DTI analysis will
be performed using the TrackVis software.
Data Monitoring
The Data Monitoring Committee (DMC) will perform data monitoring
Committee
on a regular basis, but at least annually. Study progress and
enrollment, toxicities, adverse events, risk-to-benefit ratio, and
soundness of study data, as well as other factors that can affect
study outcome will be evaluated. DM0 monitoring will also consider
factors external to the study when interpreting the data, such as
scientific or therapeutic developments that may have an impact on
_________________________
the safety of the participants or the ethics of the study.
2.2
Overview of Target Condition: Cancer Cachexia
Over 1,500,000 new diagnoses of cancer are made in the U.S. every year (4). In most
cases, this condition will have a great impact in the individuals’ survival and quality of life
(QOL). Cachexia (a complex metabolic syndrome associated with underlying illness and
characterized by loss of muscle with or without loss of fat mass (5)) is very common in
patients with cancer (6). It contributes to a decrease in functional performance, takes a
heavy toll on patients’ quality of life and is associated with poor survival (7).
Unlike what
is seen
in
diet-induced
weight loss,
cancer cachexia patients
have
diminished appetite, food intake and insulin sensitivity (8). We and others have found
several abnormalities in different hormonal axes regulating appetite and body weight in
this setting and they have been postulated to have a pathogenic role. These include
abnormalities in growth hormone/insulin-like growth factor-I (GH/IGF-I), gonadal axis,
inflammation
and
appetite
regulating
peptides
including
ghrelin,
leptin
and
other
adipokines (9-12).
Despite the significant burden that cachexia and other cancer-related symptoms such as
anorexia and poor functional status represent to cancer patients, these symptoms often
remain
undiagnosed
and
untreated.
Moreover,
there
are
currently
no
approved
treatments for cancer-related cachexia and off-label treatments used for this condition
such as appetite stimulants (e.g., megestrol acetate) are largely ineffective and are
associated with potentially serious side effects (i.e., adrenal insufficiency, hypogonadism,
deep venous thrombosis, etc.).
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2.3
Anorexia and its contribution to cancer-cachexia
Up to 80% of patients with advanced cancer experience a decrease in appetite and food
intake (13). This is caused by the tumor itself since it is present even in treatment-naïve
patients but it is usually worsened by the administration of emetogenic chemotherapy or
radiotherapy (14). Other factors that may play a role include neuropsychiatric factors such
as depression or pain, gastrointestinal obstruction and alterations in taste (15). This
decrease in appetite takes a toll in these patients’ quality of life and deeply affects the
family’s perspective on the disease.
The etiology of cancer cachexia and anorexia is not well-understood. We hypothesize
that the brain must play a major role because a) the hypothalamus is the control center
for energy homeostasis in the body and b) the striatum is the reward center that
determines how appetitive a particular food feels. To study the pathways regulating
appetite in the setting of cancer cachexia and anorexia, we will perform functional
Magnetic Resonance Imaging (fMRl) studies on cancer cachexia patients. There are no
published reports studying the different components of cancer cachexia and anorexia in
the human brain. We will assess the effects of cancer cachexia and anorexia on
hypothalamic signaling and on reward centers in the brain. We will also study the effects
of the novel ghrelin mimetic (GHS) macimorelin on brain activity related to food intake.
2.4
Ghrelin and Food Reward
A widely accepted view of feeding behavior states that it is controlled mainly by a
homeostatic element (gut peptides that work at the hypothalamic level) and hedonic
signals based
in the
striatum
(16).
In
healthy humans,
ghrelin acts both at the
hypothalamic and at the striatal levels (17) favoring food reward, the intake of palatable
food, to increase preference for caloric foods, and motivated behavior for food (18).
Nothing is known about the brain effects of ghrelin or ghrelin mimetics on brain activity
during cancer cachexia and anorexia, or the effects of this syndrome on the reward
system in the brain.
2.5
Safety of Ghrelin in the Setting of Cancer
As with all clinical trials, the issue of safety is our first priority. The GHS-R is expressed in
many normal and tumor tissues including breast, thyroid and prostate and in-vitro studies
have given conflicting results (19)(20). Administration of a growth factor such as ghrelin
or GH to tumor-bearing individuals raises potential concerns of stimulation of tumor
growth, particularly through elevation of IGF-1. However, when whole animal tumor
growth studies have been conducted to evaluate the effect of increasing GH tone, the
results have generally indicated a beneficial effect (21-23). There have been publications
implicating IGF-1 in oncogenic potential; in addition, there have been reports indicating
the therapeutic potential of the major binding protein, IGFBP-3, in attenuating oncogenic
behavior either via its ability to bind
IGF-1
or via direct, IGF-independent actions.
Consequently, it may be that the balanced effect of a growth hormone based intervention
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to increase both IGF-1 and IGFBP-3 may be responsible,
in part, for some of the
apparent discrepancies. Hanada et al.(24) tested the effects of ghrelin in a different
model of tumor-induced cachexia. In this experiment, cachexia was reversed by the
administration
of
ghrelin
and
tumor
size
remained
unchanged,
decreasing
the
tumor/carcass ratio. The composite preclinical literature indicates beneficial effects of
ghrelin-based intervention in cancer-related weight loss models; it increases lean body
mass and in some studies reduces disease progression relative to the untreated state.
More importantly, administration of ghrelin mimetics was well-tolerated and safe in
preliminary studies where approximately 40 patients with cancer-induced cachexia were
exposed for at least 3 months (25). Consequently, the overall conclusion from these
preclinical and clinical in-vivo evaluations is the likelihood that activation of GHS-R will
support and improve host function without producing detrimental effects on the underlying
malignancy.
2.6
Rationale for Macimorelin Administration in Cancer Cachexia
Macimorelin is an orally active ghrelin mimetic and growth hormone secretagogue.
Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (AKA
ghrelin receptor, GHS-R) (26, 27). Pharmacological treatment of rats and mice with
ghrelin stimulates food intake and increases body weight (28). Also, ghrelin reduces fat
oxidation and increases adiposity (29). Smith et al. have shown that Ghsr -/- mice are
refractory to the stimulatory effects of ghrelin on GH release and appetite, confirming that
the GHSR-la is a physiologically relevant ghrelin receptor (30).
Activation of GHSR-la by ghrelin mimetics (growth hormone secretagogues, GHS) also
induces GH secretion (31) and it increases food intake and body weight (32, 33). In non-
cancer patients, ghrelin mimetics increase body weight and reverse the negative nitrogen
balance induced by starvation independently of their orexigenic effects. These findings
suggest that ghrelin’s effects are not entirely mediated through an increase in appetite
and that other mechanisms, such as a decrease in energy expenditure, are involved (34).
Ghrelin administration decreases energy expenditure in non-cancer human and animal
models (35, 36). In two small groups of cancer patients, a single infusion of ghrelin was
well tolerated, increasing appetite and food intake in one of the studies (9) but not in the
other (37).
Because ghrelin is a peptide with a half-life of 30 minutes, its efficacy in humans is limited
unless it is administered parenterally as a continuous infusion. Ghrelin mimetics such as
macimorelin are non-peptidic, orally available, small molecules that have a relatively long
half-life allowing for once-a-day administration. These compounds have been in clinical
trials for over a decade and our group and others have demonstrated their safety and
efficacy (33, 38).
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2.7
Summary of Clinical Experience with Macimorelin
Macimorelin is a synthetic pseudotripeptide with GHS activity similar to ghrelin. This
compound is currently in clinical trials as a diagnostic agent for the investigation of
suspected AGHD irrespective of the cause being at the hypothalamic or pituitary level.
In toxicological studies, no organ toxicities could be identified after oral or intravenous
dosing. Toxicities were only observed after intravenous dosing with resulting extremely
high plasma levels. Toxico-kinetic data indicated that the majority of the toxicity findings
were observed at plasma levels which are about 1000 times higher as compared to the
anticipated human exposure. All findings after intravenous dosing were considered to be
irrelevant for oral dosing.
Dose recommendations for clinical use have been established for oral administration
based on PK and PD studies conducted in healthy volunteers. Macimorelin has been
given to about 100 people (52 patients with AGHD and 48 healthy subjects without GHD).
The most frequent common adverse reaction after macimorelin was dysgeusia, a
distortion of the sense of taste, reported by 12 test persons, diarrhea reported by 3
persons, and 7 other types of possible reactions in I person each. Macimorelin has been
reported to have likely caused one serious side effect in one subject to date. An
electrocardiogram that was
recorded
60
minutes
after
macimorelin
administration
indicated that the subject could be experiencing abnormal heart rhythm, although the
subject was experiencing no symptoms. The subject was hospitalized and a series of
tests were run that all indicated the subject’s heart was normal. The next day, the
abnormalities seen in the electrocardiogram the previous day were no longer present and
the subject was discharged from the hospital. In a recent trial with 28 healthy volunteers,
macimorelin was dosed
up to 4 times higher than
in our current research study.
Macimorelin was well tolerated up to the highest dose. One out of six subjects after
macimorelin 0.5 mg reported dizziness and upset stomach. Four out of 15 subjects
reported possible adverse reactions after higher doses of macimorelin. The adverse
reactions included 3 episodes of headache and one episode each of dizziness and
diarrhea.
Macimorelin is metabolized mainly by CYP3A4 but has no CYP3A4 inhibitory activity.
Therefore, macimorelin is not expected to affect the plasma concentrations of other drugs
metabolized
by CYP3A4.
Potent inhibitors or inducers of CYP3A4 may affect the
pharmacokinetic profile of macimorelin. Co-administration of potent CYP3A4 inhibitors or
inducers should be avoided. Please see the Investigators Brochure for the complete
background on this drug.
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3.0
Objectives
3.1
Primary Objective
To evaluate the safety and efficacy of repeated daily oral administration of macimorelin at
different doses for 1 week in view of a development for the treatment of cachexia based
using the following parameters:
1.
Change of body weight (kg) between day 1 and day 7
2.
Change of IGF-1 plasma levels between day 1 (prior to dosing) and day 7
3.
Change of quality of life score (Anderson Symptom Assessment Scale, FACIT-F)
between day 1 and day 7
Hypothesis: One week administration of Macimorelin will be well tolerated and will
improve
body weight,
plasma
IGF-1,
and
quality
of
life compared
to one week
administration of placebo in patients with cancer cachexia.
3.2
Secondary Objectives
1.
Food intake as measured by a food diary to be recorded for three days before days I
and 7 and by a test meal done at screening and on day 7
2.
Change of appetite measured by a validated visual analogue scale (VAS) between
screening and day 7
3.
Body composition as measured by bio-impedance analysis (BIA) and dual energy x
ray absorptiometry (D)(A) on days I and 7
4.
Muscle strength as measured by handgrip strength (HGS) and stair climbing power
(SCP)
5.
Resting energy expenditure (REE) as measured by indirect calorimetry
6.
Change in systemic blood parameters (GH, IGFBP-3, CRP, IL-6, TNF-a, and glucose)
between day I and day 7
7.
Changes in reward from food as measured by brain functional Magnetic Resonance
Imaging (fMRI)
8.
Changes in functional brain connectivity as assessed by Resting State Functional
Connectivity (RSFC) imaging and Diffusion Tensor Imaging (DTI)
Hypothesis: One week administration of Macimorelin will improve food intake, appetite,
body composition, HGS, SCP, REE, systemic blood parameters, reward from food, and
functional brain connectivity compared to one week administration of placebo in patients
with cancer cachexia.
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3.3
Safety Objectives
1.
CHnical laboratory parameters: CBC, CMP, UA
2.
Vital signs
3.
ECG changes at day 1, day 7 and post-study visit
4.
Recording of adverse events from day I to day 7
Hypothesis: One week administration of Macimorelin will be well tolerated with no serious
adverse events in patients with cancer cachexia.
4.0
Resources and Personnel
Research procedures will be conducted within the VAPSHCS at Dr. Garcia’s dedicated
research spaces and at the Clinical Research Unit (CRU). Dr. Garcia will oversee all
study
procedures
including
recruitment,
consenting,
administering
surveys,
data
analysis, and coordination of all regulatory activities. Approved study staff (i.e. research
nurses, postdoctoral fellows, study coordinators) will also carry out these procedures
under the supervision of Dr. Garcia. Dr. Garcia and approved study staff will have
access to protected health information. CRU staff may be contracted to perform study
procedures in the case of an approved study staff member being unavailable. CRU staff
will not have access to protected health information.
5.0
Study Procedures
5.1
Study Design
This is a double-blind, randomized, placebo-controlled trial to test the effects of the
ghrelin mimetic macimorelin in cancer-cachexia patients after one week of administration.
Adequate efficacy will be defined as a O.8 kg of body weight gain or a 50 ng/mL
increase in plasma IGF-1 levels or an improvement in quality of life questionnaires of at
least 15% compared to placebo. The timeline of the study procedures are as follows:
Screening:
Baseline:
Day 7:
Post-study visit:
Day -24 to
Day I
assessmentlend
14 +1- 3 days after
Day -1
of treatment
end-of-treatment
Informed Consent
X
History and exam1
X
X
X
X
AEZS-130 administration
X
X
PD2
X
X
ECG and Safety Labs3
X
X
X
X
Body Composition
Analyses4
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Functional performance
assessment5
Resting energy
expenditure6
Questionnaires7
X
X
Laboratory assays8
X
X
Appetite and food intake
assessment9
MRI
X
X1°
Adverse Events
X1°
X
X
Footnotes:
Patients will receive treatment daily between days 1 and 7. Dosing on days 1 and 7 will take
place in the clinic. Patients will take the drug at home on days 2-6. All tests will be done before dosing
unless otherwise noted.
1 Exam will include body weight measurement and a complete physical exam.
2 Pharmacodynamics (PD) will be assessed before and 1 hour after dosing with measurements of GH.
3Safety labs will include: CBC with Duff, comprehensive metabolic panel, and UA (including hCG for
females). On days 1 and 7 ECG will be performed before and 1 h after dosing.
4Tests include bioimpedance analysis and dual energy x-ray absorptiometry.
5Functional performance will be assessed by: a) handgrip strength, b) stair climbing power, c) activity level
6Resting energy expenditure will be assessed by indirect calorimetry.
7Questionnaires will include: The Eastern Cooperative Oncology Group (ECOG), and Karnofsky Scales,
Anderson Symptom Assessment Scale (ASAS) and Functional Assessment of Chronic Illness
Therapy-Fatigue (FACIT-F).
8 This will include measurements of glucose, IGF-1, GH, IGFBP-3, lL-6, CRP, and TNF-alpha.
Appetite will be assessed by a VAS before and I h after breakfast; food intake will be assessed by a food
diary. A test meal will be given at screening and I h after dosing on day 7.
10After dosing
Upon completion of the Day 1 procedures, allowing for procedure exemptions where applicable,
the subject will be paid $100 by check. Upon completion of the Day 7 procedures, allowing for
procedure exemptions where applicable, the subject will be paid an additional $100 by check.
5.2
Study Drug
Study drug (Macimorelin) will be provided at no cost by ?Eterna Zentaris (AEZS). The
Pharmaceutical Development group from AEZS has analyzed the stability of macimorelin
in Powerade® for 7 days at both room temperature (25°C) and at 2-8°C. Data indicate
that if stored refrigerated (2-8C), the solution is stable over 7 days whereas at room
temperature (25°C) it should not be stored longer than 3 days. Due to those results,
macimorelin mixed in Powerade® and Powerade® alone will be prepared in individual
doses by the MEDVAMC research pharmacy. Patients will receive macimorelin
1 mg/kg
and matching placebo (Powerade®) according to the protocol as stated above in the
study design’ section. The study staff (P1, pharmacist, or authorized study coordinator)
will dispense the product to the patients.
On day 1 and 7, patients will be dosed at the
clinical research center by the coordinator. From days 2 through 6, patients will self-
administer the drug or placebo at home. Patients will be instructed to keep these doses in
the refrigerator at 2-8°C and to drink them while fasting at least 1 hour before breakfast.
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5.3
Blinding
The allocation schedule will be stored securely; no member of the investigational team
involved in generation or review of the study database will be allowed to see the
allocation schedule or data that may otherwise unblind treatment allocations. Two sealed
envelopes will be kept for each patient. One will be kept in the Research Pharmacy and
the other in the patient’s file in case a patient needs to be unblinded. Unblinding should
be avoided to the extent possible. Unblinding should only occur in emergencies for which
knowledge of the treatment allocation will affect patient care decision-making. Formal
unblinding of the study will occur after the database is locked or if requested by the DMC.
5.4
Drug Inventory and Disposition
An exact inventory of all study drug(s), including placebo, will be maintained at the
investigational site.
The study drug(s) will be stored in a locked storage area under
environmental
conditions appropriate
for the product(s).
All study drug(s)
will
be
accounted for. Study drug(s) will only be shipped or destroyed upon written authorization
from AEZS.
5.5
Screening Visit
•
Screening evaluations will be performed within three weeks prior to the baseline visit
and may occur on different days.
Informed consent must be obtained prior to any
screening procedures.
•
Informed consent will be scanned and entered into our electronic medical records
(CPRS) as per current VA guidelines.
•
Following signature of informed consent, participants will be given a study ID using
the format: [protocol#}.[enrollment#}
•
After signing the informed consent and review of inclusion and exclusion criteria, a
complete history and physical exam (H&P) will be performed. Special emphasis will
be placed on evaluation for any signs of pedal edema, pleural effusions, and ascites.
Body weight will be obtained on a calibrated scale dedicated for this study.
Patients
will remove shoes, belts, wallets, keys, and cell phones.
Underwear and a gown will
be worn.
•
A fasting blood sample (30 mL) will be obtained to measure safety labs including a
complete blood count with differential (CBC with Differential), and comprehensive
metabolic panel, and a UA (including hCG for females).
•
An ECG also will be performed.
•
Instructions and training for the proper use of the food diary will be given during the
screening visit. Patients meeting the lIE criteria will be provided a 3-day food diary to
assess food intake 3 days prior to their baseline visit.
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•
Selection of breakfast menu options: The patient will be asked to indicate his/her food
preferences from several breakfast menu options for the test meal to be served at
screening and again at the week 1 visit. The identical meal options will be provided on
both days. A surplus of food will be provided so that availability of food does not limit
caloric consumption.
•
After informed consent but before the test meal is given, patients’ brains will be
imaged in a Phillips 3T scanner. Before starting the experiment, an investigator or
trained technician will give the patient instructions on the safety of the MRI scan. The
MRI scanner we will use differs from conventional scanners only in that the magnet
strength is 3.0 T, rather than the more typical 1.5 T magnets used in routine clinical
scanning. The patient will enter a large room where a powerful magnet is located.
Patient will be instructed to remove all jewelry and other metal-containing objects. The
patient will then be placed on a narrow table with plastic-encased metal coil close to
the head. Next, the patient will be slid into a small tunnel approximately 6 feet long
and 25 inches in diameter. The duration of the scan is approximately 30 minutes. A
small mirror will be positioned above the patient’s head so the other end of the
scanner is visible. After the patient is positioned, the table will move the patient into
the scanner itself. The patient will be in voice-communication with a technician or
investigator via an intercom, and will have access to a squeeze bulb that generates a
loud noise just in case the patient would like to be withdrawn at any point. Each
patient will undergo two scanning sessions (pre and Day7 macimorelin or placebo). A
computer display will be positioned at one end of the scanner and can be seen
through the mirror above the patient’s head. Patients will be asked to allow us to put
one or two small, soft, rubber tubes, similar to straws, into his/her mouth. The tubes
will be used to give patient small squirts of a flavored beverage while in the scanner.
Patients will simply swallow, while keeping his or her head still. Patients will be given
a CD with .gif images of their brain taken during the structural scan if it is their first
time being scanned.
•
Breakfast Test Meal: The breakfast test meal “calorie count” will be conducted to
assess the effect of study drug on stimulating food intake. Precise source documents
will be maintained recording every food item consumed during the breakfast test meal
as well as the date, start time of food consumed and the quantity of food consumed.
In order to ensure accuracy, the serving plate and every food item will be weighed in
advance of serving. The remaining food items and plate will then be re-weighed and
the weight subtracted from the original weight measured before the meal was served.
It is essential that a surplus of food is offered so that availability of food does not limit
caloric consumption. Calories for unit-dose foods (e.g., a carton of milk) will be
derived from the product label; for other foods and beverages, calories will be
calculated from a standardized software package. Appetite will be assessed by a VAS
before and 1 h after breakfast.
•
Patients will be instructed to refrain from physical activity the day before testing on
days I and 7 to avoid changes in REE that can be induced by exercise.
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•
All Information will be entered into Case Report Forms (CRF).
5.6
Day I Visit
•
A complete history and physical exam will be performed. Special emphasis will be
placed on evaluation for any signs of pedal edema, pleural effusions, and ascites.
Body weight will be obtained on a calibrated scale dedicated for this study as
indicated above.
Patients will remove shoes, belts, wallets, keys, cell phones and
any heavy clothing i.e. sweaters or sweatshirts. Underwear and a gown will be worn.
•
A fasting blood sample will be obtained before dosing to measure CBC with
Differential, comprehensive metabolic panel, glucose, IGF-1, GH, IGFBP-3,
lL-6,
CRP, and TNF-alpha and a UA (including hCG for females). A growth hormone level
will be measured again 1 hour after dosing. An aliquot of the sample will be stored for
up to 5 years after the study is completed to measure other inflammatory and
anabolic markers.
•
ECGs will be performed before dosing and again 1 hour after dosing.
•
REE will be assessed by indirect calorimetry before dosing. Briefly, patients will rest
in a supine position for at least 30 mm
before undergoing indirect calorimetry using a
ventilated hood technique. This system provides measurements of V02 and VCO2,
which have an error of less than 4% (39). This method is termed ‘indirect’ as the
method of collection of gas is from a transparent hood placed over the head of the
patient. One end of this hood is connected to the indirect calorimeter to measure CO2
and 02 content in the expired air. Air is drawn in from the other end of the tube, from
which a portion is sampled to measure CO2 and 02 in the inspired air. Measurements
were performed for at least 30 minutes. The measurements performed in the last 20
minutes will be averaged to calculate REE using the Weir equation (40). This method
is currently considered one of the
‘gold standard’
methods to assess energy
expenditure. Respiratory quotient (VCO2 NO2 ratio, RQ) will also be calculated as a
measure of relative utilization of carbohydrates and fat.
•
Body composition will be measured by BIA and
DXA before dosing.
BIA is a
noninvasive method of estimating body composition based on the ability of tissues to
conduct an electrical current. Based on this principle, lean tissue conducts electricity
better than fat; therefore, the body composition analyzer/scale is able to calculate
total body water, total body fat and total body lean mass. DXA scan uses a low
amount of radiation to determine fat mass and bone mass and calculates fat-free
mass (whole body and segmental).
•
Functional performance will be assessed before dosing by: a) HGS and b) SCP.
These tests have been shown to correlate with V02 max and are good tests of
aerobic and functional capacity in cachectic states (41, 42). Briefly, HGS will be
measured by a handheld dynamometer (Jamar Hydraulic Dynamometer, J.A. Preston
Corp., Clifton, NJ) as described elsewhere (43). SCP, which allows measuring the
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maximal anaerobic power of the involved muscles, will be performed as follows. At
the moment of the first execution, 2—3 practice trials will be allowed so that the
patients gained a good control of the performing technique. SCP consists in a
modification of the test proposed by Margaria et al, (44), recently applied in elderly
patients (45). In brief, patients will be invited to climb up ordinary stairs at the highest
possible speed, according to their capabilities. The stairs will consist of 13 steps of
15.3cm each, thus covering a total vertical distance of 1.99 m. An experimenter will
measure the time employed to cover the test with a digital stopwatch. In line with
Margaria et al. (44), assumptions, anaerobic power (in W) will be calculated by using
the following formula: “body mass x 9.81 x vertical distance/time where body mass,
vertical distance (i.e., 1.99 m) and time are expressed in kg, m and s, respectively,
and
9.81
m/s2 represents the acceleration of gravity.
Physical activity will be
monitored from
Day
1
to Day 7 with the Actical Version 3.0 activity monitor
(Respironics Inc., Murrysville, PA). The wrist-worn monitor will be provided on Day 1,
along with verbal instructions for proper use, and worn for the entire 7-day study
period until it is returned to study staff on the Day 7 visit.
•
Previously validated questionnaires including the ECOG and Karnofsky scales will be
administered. Patients will also complete the ASAS and FACIT-F questionnaires to
assess changes in symptoms that play a role in performance such as fatigue.
•
Food diary will be retrieved and information entered into the ORE. A new food diary
will be given and patients asked to complete it 3 days before the next visit.
•
Patients will be randomized as indicated above to placebo or macimorelin. All
patients will receive the first dose before being discharged. Patients will be instructed
to keep the drug in the refrigerator at 2-8° C and to take the drug on an empty
stomach in the morning at least
1 h before breakfast, because it was previously
demonstrated that the administration of macimorelin with food significantly reduced
its GH secretagogue efficiency and bioavailability. The research Pharmacy will
provide each patient with 5 syringes (days 2 through 6) with either Powerade® alone
(placebo) or macimorelin diluted in the same volume of Powerade®. Patients will be
also
provided
with
a
bag
and asked
to
return the empty syringes
for drug
accountability.
•
Patients will be asked to refrain from physical activity the day before the next visit to
avoid changes in REE that can be induced by exercise. Patients will be asked not to
take the dose of study drug the day of the Day 7 visit.
•
All Information will be entered into CRFs.
5.7
Day 7 Visit
•
The Actical activity monitor will be returned to study staff at the beginning of this visit.
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•
A complete history and physical exam will be performed as indicated above. Special
emphasis will be placed on evaluation for AEs and any signs of pedal edema, pleural
effusions, and ascites. Body weight will be obtained on calibrated scale dedicated for
this study as indicated above.
Patients will remove shoes, belts, wallets, keys, cell
phones and any heavy clothing i.e. sweaters or sweatshirts. Underwear and a gown
will be worn.
•
A fasting
blood sample will be obtained before dosing to measure CBC with
Differential, comprehensive metabolic panel, glucose, IGF-1, GH, IGFBP-3, lL-6,
CRP, and TNF-alpha and UA (including hOG for females). A growth hormone level
will be measured again 1 hour after dosing. An aliquot of the sample will be stored for
up to 5 years after the study is completed to measure other inflammatory and
anabolic markers.
•
ECGs will be performed before dosing and again 1 hour after dosing.
•
REE, BIA, DXA, HGS, and SCP will be assessed as indicated above.
•
Questionnaires including the ECOG and Karnofsky scales will be administered.
Patients will also complete the ASAS and FACIT-F questionnaires to assess changes
in symptoms that play a role in performance such as fatigue. Patients will receive at
this time the study drug dose.
•
A new MRI session (equal to the one on Screening Visit) will be administered
approximately 45 minutes after dosing but before the test meal.
•
Breakfast Test Meal will be provided 1 .5 hours after dosing with the same items and
amount provided at the screening visit. Appetite will be assessed by a VAS before
and I h after breakfast. Food diary will also be retrieved at this visit.
•
Blood samples for GH measurements will be obtained lh after dosing.
•
Drug accountability will be assessed by counting the number of empty syringes that
the patient returned.
•
All Information will be entered into CRFs.
5.8
Post-Study Visit
•
An H&P will be repeated by the P1 with special emphasis on AEs. A fasting blood
sample will be collected as previously described for measurement of safety labs
including CBC with Diff, comprehensive metabolic panel, hOG (for females), UA. An
ECG will be performed.
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5.9
Recruitment Methods
Eight total participants who complete the entire protocol are needed. Participants will
be recruited from the Oncology clinic through our collaborator Dr. Wu and his clinical
staff as follows:
•
Study staff accesses medical records to identify potential participants from oncology
clinic
•
Study staff reviews records to ascertain initial inclusion/exclusion criteria
•
Study staff sends list of potential participants to clinical staff
•
Clinical staff brings up potential research study to patient at clinical visit and asks if
they’re interested in learning more
•
Study staff then speaks with patients to provide more information
•
If patient is interested they sign a consent form
•
Screening/baseline visit occurs
5.10
Informed Consent Procedure
•
The P1 and his staff will consent patients. Patients will be identified through analysis of
electronic medical records at the VAPSHCS by our collaborator, the Oncologists, and
the research staff. Patients will be approached by study staff at their cancer clinic
after clinical staff brings up potential research study to patient at clinical visit and asks
if they’re interested in learning more. Patients are offered the informed consent form
for consideration of volunteering for the study. Staff will explain the study to patients,
providing a signed copy of the consent for their records. Patients will be assured of
the voluntary nature of the trial and a member of the research staff will be available to
answer all questions regarding the study. We will emphasize that their decision to
participate in the clinical trial will not affect their treatment.
•
A waiver of consent is requested for identification/screening. The use or disclosure of
protected health information involves no more than minimal risk to the individuals and
the waiver will not adversely affect the privacy rights and the welfare of the
individuals. The risk is minimal because: 1) only trained personnel will have access to
this information, 2) information will be accessed only from our research office at the
VA and kept in a locked cabinet behind locked doors or in password-protected
computers and 3) only information absolutely required for research will be obtained
and recorded (full medical history, name, date of birth, and last 4 numbers of the
SSN).The research could not practicably be conducted without this waiver and could
not practicably be conducted without access to and use of the protected health
information because accessing potential patients’ medical records and their last 4
digits of their SSN and name is required to approach them to explain the proposed
research and consent them.
•
An adequate plan exists in order to protect health information (PHI) identifiers from
improper use and disclosure to minimize the
risk of loss of confidentiality as
recommended by VA guidelines. Adequate written assurances exist in order to ensure
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that the PHI will not be reused or disclosed to (shared with) any other person or entity,
except as required by law, for authorized oversight of the research study, or for other
research for which the use or disclosure of the PHI would be permitted under the
Privacy Rule to minimize the risk of loss of confidentiality as recommended by VA
guidelines.
•
Study personnel will be trained regarding human subjects’ protections requirements
and how to obtain and document informed consent as it is required by local and
Federal VA guidelines. All study documents containing PHI will be kept in a locked
cabinet inside a locked room. No data containing PHI will be accessible outside the
study site. The room is kept locked with the door shut. No patient data is left out of the
cabinets. Confidential information will be stored on servers managed and maintained
by the VA-IT program. All computers are password protected.
•
Sub-investigators will be provided the participant study number and de-identified (all
18 HIPAA identifiers will be removed prior to sending data outside the VA) study data
for analysis. No sensitive information will be share and the data will be transferred
electronically via secure email. No social security numbers will be requested from
patients or potential patients via phone.
•
The P1, VA collaborators, research staff, and VA research compliance monitors will
have access
to
identifiable
information.
People who ensure
quality
from
the
institutions where the research is being done, federal and other regulatory agencies
will have access to all of the research data. No else will have access to identifiable
research data. An Accounting of Disclosure (AOD) will be created and maintained for
any disclosure of individually identifiable information (Ill) outside the VA. The manual
spreadsheet will include the date of the disclosure, nature or description of the Ill
disclosed, purpose of each disclosure and the name and address of person or agency
to which the disclosure was made.
5.11
Inclusion/Exclusion Criteria
5.11.1 Inclusion Criteria
1.
Patients 18 years of age with histological diagnosis of active solid or
hematological malignancies
2. ECOG performance status of 0-2,
3.
Presence of cancer-related cachexia defined as an involuntary weight loss of
at least 5% over the previous 6 months, 10% over the previous 12 months or 2%
over the previous 6 months with a BMI<20, and
4. Provide written informed consent prior to screening.
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5.11.2 Exclusion Criteria
1. Obesity (body weight >140 Kg);
2. Recent active excessive alcohol or illicit drug use;
3. Severe depression as determined by the investigator;
4. Other causes of cachexia such as: Liver disease (AST or ALT > 3x normal
levels); renal failure (creatinine > 1.5 mg/dL), untreated thyroid disease, class Ill-
IV CHF, AIDS, severe COPD requiring use of home 02;
5.
Inability to increase food intake (e.g., esophageal obstruction, intractable
nausea and vomiting);
6.
Any condition that would prevent the patient from performing the research
procedures (e.g., unstable coronary artery disease);
7.
Use of growth hormone, megestrol, Marinol, or any other anabolic agents,
appetite stimulants, tube feeding, or parenteral nutrition during the 1 month prior
to entering the study;
8.
Systemic corticosteroids
administration
for
>
6 days
a
month
(i.e.daily
continuous schedule).
9.
Recent administration (less than 1 week) of highly emetogenic chemotherapy
(Hesketh scale class 4-5); patients may otherwise be undergoing chemotherapy.
10. Being female and pregnant, breast-feeding or of childbearing potential. (Note:
Lack of childbearing potential for female patients is satisfied by: a) being post-
menopausal; b) being surgically sterile; C) practicing contraception with an oral
contraceptive, intra-uterine device, diaphragm, or condom with spermicide for the
duration of the study; or d) being sexually inactive. Confirmation that the patient is
not pregnant will be established by a negative urine hCG pregnancy test at the
time of enrollment.
11. Co-administration of drugs that prolong QT interval (Appendix II), CYP3A4
inducers (Appendix Ill), QTc equal to greater than 450ms at screening or other
investigational agents (a wash-out period of five times the half-life of drugs that
prolong QT will be allowed with approval of prescriber).
12. Conditions that would preclude from successfully scanning patients in MRI: a.
Claustrophobia (this would make lying in the scanner very uncomfortable); b.
having a pacemaker, aneurysm clips, neurostimulators, cochlear implants, metal
in eyes, steel worker, or other implants; c. History of Seizures; d. History of head
injuries resulting in loss of consciousness > 10 minutes.
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5.12
Study Evaluations
5.12.1 Quality of Life Measures
The study will include the following patient-reported Quality of Life Instruments:
ASAS and FACIT-F. These instruments have been previously used and validated
in clinical research investigations. These instruments must be completed by the
patient before other procedures are done at follow-up visits. When the patient has
completed the questionnaires, the forms will be collected from the patient and
entered into the case report forms (CRFs) by authorized site personnel.
Site
personnel should review the forms to ensure all questions were answered and
that the intended answers were clearly marked before the patient leaves the study
site. The site personnel should ask the patient to complete any missed questions
and to clarify any unclear answers.
If a patient is unable to complete any or all of
the questions, the reason must be documented in the source documentation and
in the CRF.
5.12.2 Cardiac Assessment
Cardiac assessment includes a 12-lead ECG test.
Electrocardiogram testing will
be performed on all patients. ECG will be performed during the post-study visit.
5.12.3 Laboratory Assessments
All hematology, blood chemistries, urinalysis, serum/urine pregnancy tests (if
applicable) will be performed by the local laboratory at the investigational site.
5.12.4 Handgrip Strength Testing
HGS determination will be performed using a hand-held dynamometer. On each
occasion that HGS is measured, the measurement will be made three times for
each hand: 3 measurements for the right hand, followed by 3 measurements for
the left hand. A rest period of at least 30 seconds will take place between each
individual measurement. During measurement of HGS, the participant should be
asked to remove any jewelry that would prevent him/her from exerting maximum
squeezing force with either hand. Patient is seated on a chair with feet flat on the
floor and facing table/desk. Patient holds dynamometer vertically, supported by
table/desk, with elbow flexed approx. 900. Patient will squeeze the dynamometer
with
the
maximum
force
for
up
to
four seconds,
during
which
time the
administrator says “Squeeze as hard as you can!” and, as patient squeezes
“harder!.. harder!”, and “relax.”
5.12.5 Body Composition
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Weight will be measured using the calibrated scale dedicated for use in this study.
This and all other weights will be collected with the patient wearing only a hospital
gown or hospital scrubs (and, if desired, underwear). Patients must be barefoot
when weighed. All weights will be recorded in kilograms. Values collected using
other scales or other procedures
(e.g.,
while wearing
heavy clothing) are
prohibited for the purpose of this trial.
BIA and DXA will be performed in an effort to gain insight into the practicality of
this methodology and to gain insight into the relationship of body weight changes
relative to body composition changes. BIA is a noninvasive method of estimating
body composition based on the ability of tissues to conduct an electrical current.
Based on this principle, lean tissue conducts electricity better than fat; therefore,
the body composition analyzer/scale is able to calculate total body water, total
body fat and total body lean mass. DXA scan uses a low amount of radiation to
determine fat mass and bone mass and calculates fat-free mass (whole body and
segmental).
5.12.6 Biomarkers
Serum samples for all biomarker determination (IL-6, TNF-cL, CRP, GH, IGF-1,
IGFBP-3) will be drawn and processed at the research site lab.
5.12.7 Physician-Reported Instruments
Patients
will
be evaluated
for performance
using the
Eastern
Cooperative
Oncology Group (ECOG), and Karnofsky Scales, at each visit (see Appendices II
and Ill).
5.12.8 Indirect Calorimetry
Resting energy expenditure will be measured by indirect calorimetry. Following an
overnight fast, patients will rest in a supine position for at least 30 mm
before
undergoing indirect calorimetry using a ventilated hood technique. This method is
termed ‘indirect’ as the method of collection of gas is from a transparent hood
placed over the head of the patient. One end of this hood is connected to the
indirect calorimeter to measure carbon dioxide and oxygen content in the expired
air, and air is drawn in from the other end of the tube, from which a portion is
sampled to measure oxygen and carbon dioxide in the inspired air.
Measurements
will
be
performed
for at least
30
mm.
The measurements
performed in the last 20 mm
will be averaged to calculate REE using the Weir
equation (40). This method is currently considered one of the ‘gold standard’
methods to assess energy expenditure. Respiratory quotient (VCO2 NO2 ratio,
RQ) will be calculated as a measure of relative utilization of carbohydrates and fat.
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5.12.9 Stair Climbing Power
The patients will be instructed to ascend a standard flight of stairs as quickly as
possible, using the handrail if necessary. Time will be recorded to the nearest 0.01
second. The power is calculated in watts by dividing the time elapsed into the
product of the body weight, the vertical distance, and the acceleration of gravity
(9.8 m/secsec).
5.12.10 Laboratory assays
Serum samples for all biomarker determination (IL-6, TNF-ci, GH, IGF-1, IGFBP
3) will be drawn and processed at the research site lab.
5.12.11 Test Meal
Food intake will be measured as a secondary outcome by a free-choice test meal
and a food diary. After signing an informed consent, trained personnel will instruct
patients on the use of the food diary, review food preferences and perform the
food intake analysis. Based on this information, patients will be given free access
to food items of their like and instructed to eat as much as they want. This
procedure will take place at screening after signing informed consent and review
of
lIE criteria and on day 7 one (1) hour after dosing. The same food items and
amounts will be provided at each meal. Food items will be weighed before and
after each test meal and total calories as well as the relative proportion of fat,
carbohydrates (CHO) and protein will be measured using FoodWorks version 7.01
(TNC, Long Valley NJ, USA). Changes from baseline in Kcal, fat, CHO and
protein consumed will be measured and placebo-treated patients will serve as
controls.
We will use a food diary detailing intake for 3 consecutive days (including
1
weekend day and 2 weekdays) to assess patients’ nutrient intake and eating
patterns. This method has been shown to adequately reflect current dietary intake
in this population (2). This diary consists of 6 fields to be completed each day,
corresponding to 3 main meals (breakfast, lunch, and dinner) and 3 between-meal
snacks
(morning,
afternoon,
and
evening).
Trained
personnel
wifl
instruct
participants on completion of the food record and later review the records with
each participant for accuracy and completeness. Each patient will be asked to
complete this diary the week before starting treatment and again three days
before the Day 7 visit. Analysis will be done using FoodWorks version 7.01 and
will focus on energy intake and the percentage of total energy contributions (% of
kcal) from fat, carbohydrate, and protein. Mean intake will be expressed per
person per day and per kg of body weight. Mean changes from baseline will be
compared between patients randomized to Macimorelin vs. placebo.
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5.12.12 Imaging
Imaging will be performed with a 3-Tesla Phillips MRI located at the University of
Washington. Patients will lay still for -30 mm
in the scanner. The only instruction
is that they should swallow little squirts of juice (0.8 ml, just enough to taste the
juice) several times, while keeping eyes open and being as still as possible.
Imaging data will be analyzed separately for fMRl, DTI and DSFC. Correlations
between different imaging modalities and between imaging data and behavioral
and physiological measures will be used to extract meaningful biological data.
5.12.13 Data Analysis
5.12.13.1 Statistical Analyses
This is a pilot and exploratory study to assess safety and efficacy. The
data generated through this trial will be used to power a future, larger
clinical trial. All efficacy variables will be summarized descriptively by
treatment using N, mean, SEM and standard deviation. Data from placebo-
receiving patients from all groups will be pooled together for the purpose of
analyses since their treatment will be identical. Analyses will be done as
changes from baseline using paired t-test for continuous variables and
Fisher’s exact test for categorical variables. Also, one-way ANOVA will be
used to compare the differences in outcomes between groups. Appropriate
transformations will be applied
to the outcome changes to improve
distribution
toward
normality.
As
recommended
by
the
CONSORT
guidelines (1), we will develop both completers and intention-to-treat (ITT)
models.
We have selected primary endpoints for each specific aim based on the
clinical relevance of each outcome and the research questions proposed.
Other endpoints will be considered secondary endpoints that will provide
supplemental evidence to the conclusions drawn from these primary
variables or will explore different areas. Full disclosure and complete
description of all endpoints will be included in public presentations of data
to avoid bias. Safety, including adverse events, ECGs, vital signs, and
laboratory assessments will be summarized descriptively by treatment
group.
Analysis of fMRI data will be as follows: We use a general linear model in
analyzing and designing our fMRI experiments. To compare data from
different patients, the scan data from each patient must be transformed
into
a
standard
anatomical
framework.
We
follow the
approach
of
Frackowiak et al (46) which analyzes the brain into small local volumes, or
“voxels.’ The fMRI signal from each voxel
is then subjected to the
following transformation and analysis steps:
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-Analysis Step 1: Spatio-temporal normalization to a standard brain map,
and smoothing to improve the signal to noise ratio.
-Analysis Step 2: Statistical analysis to determine the significance of the
activity measured
at each
voxel.
We
use an established statistical
framework (2, 3) in terms of a general linear model, which incorporates
and formalizes the independent explanatory variables in our experiment.
Given the variance of each parameter, we can construct a t-statistic as a
measure of the significance of differences in the parameters estimated
from different experiments, at different voxels, or in different patients. In
practice, we construct a t-statistic out of a particular linear combination of
the parameters that describes a quantity of interest. To express this
mathematically,
we
define a contrast vector that specifies
a
linear
combination of parameters. Then the t-statistic is the quantity of interest
divided by its standard error. When we calculate a t-statistic at each voxel
in an imaged brain, measuring the significance of a difference between
parameters from different patients or different experimental conditions, the
resulting set is called a statistical parametric map. We use such maps to
determine areas of significant activation in the brain during presentation of
stimuli or performance of the task. DTI analysis will be performed using the
TrackVis software.
5.12.13.2 Study Endpoints
Primary efficacy parameters:
•
Change of body weight (kg) between day I and day 7
•
Change of IGF-1 plasma levels between day 1 (prior to dose) and day 7
•
Change of quality of life score (Anderson Symptom Assessment Scale,
FACIT-F) between day I and day 7
Secondary efficacy parameters:
•
Food intake as measured by a food diary to be recorded for 3 days
before days 1 and 7 and by a test meal administered at screening and
on day 7.
•
Change of appetite measured by a validated visual analogue scale
between day 1 and day 7.
•
Body composition as measured by bio-impedance on days 1 and 7.
•
Muscle strength as measured by handgrip strength and stair climbing
power.
•
Energy expenditure as measured by indirect calorimetry.
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•
Change in GH, IGFBP-3, CRP, IL-6 and TNF-a and glucose between
day 1 and day 7.
•
Changes in reward from food as measured by brain functional Magnetic
Resonance Imaging (fMRl).
•
Changes in functional brain connectivity as assessed by Resting State
Functional Connectivity (RSFC) imaging and Diffusion Tensor Imaging
(DT I).
Safety parameters:
•
Clinical
laboratory
parameters:
complete
blood
count
(CBC),
comprehensive metabolic panel (CMP), urinalysis (UA)
•
Vital signs,
•
Electrocardiogram (ECG) changes pre and post-dosing at day
1 and
day 7 and on the post-study visit.
•
Recording of adverse events from day I to day 7
5.12.1 3.3 Statistical Analyses
Safety,
including
adverse events,
ECGs,
vital
signs,
and
laboratory
assessments will be summarized by treatment group. All safety analyses
will
be
performed
on
the
ITT population.
For continuous
variables,
descriptive statistics including the number of observations (N), mean,
standard deviation, minimum, and the maximum will be presented for the
values as well as for the change from baseline by treatment group at each
time point. Treatment-emergent adverse events (TEAEs) are defined as
those adverse events that start on or after the first dose of randomized
study drug. The number and percent of patients reporting TEAEs, grouped
by MedDRA system organ class and preferred term, will be tabulated by
treatment group.
Summaries will also be provided by maximum severity
for the number and percentage of patients with TEAEs and for patients
with drug-related TEAEs by system organ class, preferred term, and
treatment group. Serious adverse events and adverse events leading to
discontinuation will be summarized in a similar fashion. Vital signs at each
time point and changes from baseline will be summarized by treatment
group. Laboratory results of interest will be summarized by treatment
group using frequencies and percentages.
MRI has been repeatedly
shown to be extremely safe. In fact, there is no reason to believe that the
scanners can cause any undesirable effect. Safety precautions, however,
are very important. The scanners are very strong electromagnets and any
piece of metal inside the scanner room could potentially be a hazard. We
are equipped with metal detectors (both in the room’s door and wand style)
and extensively query patients about the possibility of metals inside their
bodies (pins, staples, etc).
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5.12.14 Withdrawal of Participants
It is unlikely that participants will be withdrawn without their consent. This may
happen if the sponsor or regulatory authorities (VA) decide to terminate the study.
Participation is completely voluntary and patients may withdraw from this study at
any time without any negative consequences or penalty for study withdrawal. To
withdraw, patients will be instructed to advise study staff directly by calling the
number in the consent form. The participant will not have the option to get the
remaining portion of their sample back. Samples will not be destroyed but the
sample will be kept anonymously and used for analysis. Patients may withdraw
their consent and discontinue at any time with verbal or written notification to the
investigators. Patients will be encouraged to complete the final endpoint and post-
study visit procedures if possible.
6.0
Reporting
The Investigator is responsible for monitoring the safety of patients who have enrolled in the
study. The investigator will grade adverse events using the NCI-CTCAE, Version 4 (Appendix I).
All adverse events occurring after any administration of the study drug through the 16 day post-
treatment follow-up visit will be followed
until the event resolves,
until the patient begins
alternative.
However, certain adverse events (e.g., a cerebrovascular accident, worsening
hypertension) will not be expected to resolve completely; in these cases, the date and time
should be recorded when the event reaches its new, stable equilibrium and any remaining
residua of the event should be documented.
The investigator is required to document all adverse events occurring during the clinical trial,
commencing with the first dose of study drug through the 16 day post-treatment follow-up visit.
Adverse events occurring following the signature of the informed consent, but prior to the first
dose of study drug will not be reported as adverse events, but will be captured as medical
history. The adverse event reporting period also ends if the patient begins an alternative therapy
within 16 days of the last administration of study drug. It is also important to record all adverse
events that result in permanent discontinuation of Macimorelin, whether serious or non-serious.
All serious adverse events will be reported within 24 hours of study staff being made aware of
the event,
to AEZS. All serious adverse events will be reported within 7 calendar days of study
staff being made aware of the event to FDA for fatal or life-threatening events and within 15
calendar days of study staff being make aware of the event to FDA for all other serious adverse
events. Serious adverse events will also be reported within 5 business days of study staff being
made aware of the event to RB per posted guidelines (immediate oral notification will be made
to IRB in the case of local death). The DMC will be notified via secured email according to the
same regulations as reporting to RB.
Any untoward or unfavorable event occurring following administration of study drug, whether or
not it is considered to be related to the study drug will be considered an adverse event (AE). An
AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally
associated with the use of a medicinal (investigational) product, whether or not considered
related to the medicinal (investigational) product. All AEs, including observed or volunteered
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problems, complaints, or symptoms, are to be entered into the paper CRFs.
Each AE is to be
evaluated for duration, intensity, and causal relationship with the study medication or other
factors. A non-serious AE is any untoward medical occurrence that does not meet any of the
criteria for serious AEs. A worsening of a pre-existing condition will be considered an AE as well.
A pre-existing condition which occurs with a known temporal frequency and severity (e.g.,
dysmenorrhea) following drug exposure will not be considered an adverse event unless the
pattern or severity has changed.
Patients should be instructed to report any AE that they experience to the Investigator. The
investigator should assess for AE at each visit.
AEs occurring during the clinical trial and the
follow-up period should be recorded. To capture the most potentially relevant safety information
during a clinical trial, it is important that the investigator record accurate AE terms on the paper
CRFs.
Whenever possible, a specific disease or syndrome rather than individual associated signs and
symptoms should be identified by the Investigator and recorded.
However, if an observed or
reported sign or symptom is not considered a component of a specific disease or syndrome by
the Investigator, it should be recorded as a separate adverse event.
•
Seriousness: A serious adverse event (SAE) is any AE that: results in death, permanent
or significant disability, hospitalization or a prolongation of an existing hospitalization; is a
congenital anomaly/birth defect; or is otherwise medically alarming.
•
Severity: All adverse events will be rated according to the National Cancer Institute (NCI)
Common Toxicity Criteria (CTCAE v4.O, Appendix I).
•
RelationshiD to Study Drug: All adverse events will be assessed by the Investigator to
establish the presumed causal relationship with the study drug considering: a) Temporal
relationship, b) Pattern consistent with known drug effect and c) Presence of other
potential etiologies.
Adverse events will be assigned one of the following causal
relationships:
o
Unrelated: The study drug almost certainly (or certainly) did not cause the event.
Guidelines: There is no reasonable temporal relationship of the event to the
administration of drug; the pattern is inconsistent with that known for the drug;
and/or there is another obvious etiology.
o
Probably not related: It is more likely that the event is due to another etiology than
due to the study drug.
Guidelines: There is no reasonable temporal relationship
of the event to the administration of drug; the pattern is inconsistent with that
known for the drug; and/or there is another more likely etiology.
o
Possibly Related: It is equally likely that the event is due to the study drug as it is
due to another etiology.
Guidelines: There is a reasonable temporal relationship
of the event to the study drug; the drug seems as likely as other etiologies to have
caused the effect.
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o
Probably Related: It is more likely that the event is due to the study drug than due
to another etiology. Guidelines: There is a reasonable tempora’ relationship of the
event to the study drug; the event may be consistent with a known pattern of drug
(or drug class) effects; the drug seems more likely than other etiologies to cause
the effect; the adverse event diminished upon cessation of study drug exposure or
reduction
in
dose;
and/or the adverse
event worsened
or recurred
upon
unintentional re-exposure to the study drug (Intentional rechallenge for the
purpose of assigning causality should not be performed).
o
Definitely Related: The evidence is compelling that the study drug caused the
adverse event.
Guidelines: there is a reasonable temporal relationship of the
event to the study drug; the event is consistent with a known pattern of drug (or
drug class) effects; the drug is far more likely than other etiologies to have caused
the effect; the adverse event diminished upon cessation of study drug exposure or
reduction in dose; the adverse event worsened or recurred upon unintentional re
exposure to the study drug (Intentional rechallenge for the purpose of assigning
causality should not be performed).
o
Unknown: The data are inadequate to assign any of the above causal relationship
categories to the study drug.
•
Monitoring Adverse Events: Patients will be monitored for the onset of AEs throughout
the course of the study from the time of first exposure to the study drug until the post-
study visit. Any ongoing AE will be assessed at appropriate frequency to document the
date and time of resolution of the event. All events will be followed to resolution even if
ongoing at the post-study visit. Certain AEs (e.g., a cerebrovascular accident) will not be
expected to resolve completely; in these cases, the date and time will be recorded when
the event reaches its new, stable equilibrium and any remaining residua of the event will
be documented. All AEs will be followed until resolution or until stable in cases where
permanent sequelae are expected.
•
Serious Adverse Event Reporting:
A SAE (per 21
CFR §312.32)
is any adverse
experience occurring at any dose that results in any of the following outcomes:
o
Death
o
A life-threatening adverse drug experience
o
Inpatient hospitalization or prolongation of existing hospitalization
o
A persistent or significant disability/incapacity
o
A congenital anomaly/birth defect
All serious adverse events will be reported within 24 hours of study staff being made
aware of the event, to AEZS. All serious adverse events will be reported within 7 calendar
days of study staff being made aware of the event to FDA for fatal or life-threatening
events and within 15 calendar days of study staff being make aware of the event to FDA
for all other serious adverse events. Serious adverse events will also be reported within 5
business days of study staff being made aware of the event to IRB per posted guidelines
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(immediate oral notification will be made to IRB in the case of local death). The DMC will
be notified via secured email according to the same regulations as reporting to IRB. This
reporting requirement is mandatory regardless of whether the event is considered to be
drug related or not.
Important medical events may be considered an SAE based upon appropriate medical
judgment. They may jeopardize the patient(s) and may require medical or surgical
intervention to prevent one of the outcomes listed above. For all SAEs occurring during
the study or within 16 days of the last administration of study drug, the Investigator must
submit follow-up reports to AEZS or its representative regarding the status of the SAE
and the patient’s subsequent course until the SAE has subsided, or until the condition
stabilizes (in the case of persistent impairment), the patient receives alternative therapy,
or the patient dies. Follow-up reporting is done by faxing in SAE follow up reports.
AEZS must also be notified of any patient who becomes pregnant or their partner who
becomes pregnant, while participating in a clinical trial. The Investigator must immediately
notify the IRB and AEZS of any pregnancy associated with study medication exposure (at
least 6 half-lives after drug administration) and record the event.
Protocol-required
procedures
for
study
discontinuation
must
be
performed
on
the
patient
unless
contraindicated by pregnancy.
All pregnancies must be followed to conclusion to
determine their outcome. Infants should be followed for a minimum of 8 weeks.
7.0
Privacy and Confidentiality
Data collected in this VA research study, including identifiers will be maintained for at
least 15 years by the VA facility. All study documents containing PHI will be kept in a
locked cabinet inside a locked room. No data containing PHI will be accessible outside
the study site. The room is kept locked with the door shut. No patient data is left out of the
cabinets. Confidential information will be stored on servers managed and maintained by
the VA-IT program. All computers are password protected. Sub-investigators will be
provided the patient study number and de-identified (all 18 HIPAA identifiers will be
removed prior to sending data outside the VA) study data for analysis. No sensitive
information will be share and the data will be transferred electronically via secure email.
No social security numbers will be requested from patients or potential patients via phone.
AA0048 is the room number for the room in Health Sciences at UW Medical Center Disc
Lab where the server for MRI data and physical MRI screening forms will be held; MRI
data will be held on an encrypted server located at UW
8.0
Information Security and Data StoragelMovement
Source documents are the records maintained that represent the first written or electronic record
of patient information. Source documents include signed
informed consent forms, written
progress notes, laboratory reports, ECG tracings, etc. All source documents must be maintained
in the secured laboratory or office space. Source documents should be recorded in blue or black
ink. Any corrections should be made by a single line drawn through the entry, adding the correct
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information, initialing and dating by the person making the change, and (preferably) indicating
why the change was required.
Paper case report forms will be used for this study. The Investigator will ensure that all data are
captured on the CRFs promptly, completely, accurately, and conform to source documents. All
OREs will be kept with the corresponding source documents in separate patient files maintained
in the secured laboratory or office space. CRFs will be transposed into electronic databases to
be stored on the appropriate secured drive at the VA.
Regulatory agencies require retention of study records for 15 years following the termination of
all clinical activities with the study drug or 15 years following approval of the product for
marketing.
Since the investigator may not be aware of the date when a product is approved or
withdrawn, all study-related records, including all source documents and all case report forms
must be maintained for at least 15 years.
9.0
References
1.
Begg C, Cho M, Eastwood 5, Horton R, Moher D, 01km
I, Pitkin R, Rennie D, Schulz
KF, Simel D, Stroup DF 1996 Improving the quality of reporting of randomized controlled
trials. The CONSORT statement. Jama 276:637-639
2.
Friston KJ, Frith CD, Frackowiak RS, Turner R 1995 Characterizing dynamic brain
responses with fMRI: a multivariate approach. Neuroimage 2:166-1 72
3.
Friston KJ, Holmes AP, Price CJ, Buchel C, Worsley KJ 1999 Multisubject fMRl
studies and conjunction analyses. Neuroimage 10:385-396
4.
Jemal A, Siegel R, Xu R, Ward E 2010 Cancer statistics, 2010. CA Cancer J Clin
60:277-300
5.
Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar
Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A,
Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D,
Wolfe R, Anker SD 2008 Cachexia: a new definition. Clin Nutr 27:793-799
6.
Levine JA, Morgan MY 1998 Preservation of macronutrient preferences
in cancer
anorexia. Br J Cancer 78:579-581
7.
Maltoni M, Nanni 0, Pirovano M, Scarpi E, Indelli M, Martini C, Monti M, Arnoldi E,
Piva L, Ravaioli A, Cruciani G, Labianca R, Amadori D 1999 Successful validation of
the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study
Group on Palliative Care. J Pain Symptom Manage 17:240-247
8.
McCall JL, Tuckey JA, Parry BR 1992 Serum tumour necrosis factor alpha and insulin
resistance in gastrointestinal cancer. BrJ Surg 79:1361-1363
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9.
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APPENDIX I: NCI-CTCAE, VERSION 4
The
Revised
National
Cancer
Institute
Cancer
Therapy
Evaluation
Program
Common
Terminology
Criteria
for
Adverse
Events,
Version
4
may
be
viewed
online
at:
http:!!ctep.cancer.gov/reortincj!ctc. html
APPENDIX II: DRUGS THAT PROLONG THE QT INTERVAL
http://www.azcert.orci/advisorv-committee.cfm
Generic Name! Name Class/Clinical Use Comments
Clomipramine Anafranil® Tricyclic Antidepressant! depression
Trimethoprim
Sulfa Bactrim® Antibiotic! bacterial infection
Diphenhydramine Benadryl® Antihistamine / Allergic rhinitis, insomnia
Citalopram Celexa® Anti-depressant I depression
Ciprotloxacin Cipro® Antibiotic / bacterial infection
Trazodone Desyrel® Anti-depressant / Depression,insomnia
Fluconazole Diflucan® Anti-fungal! fungal infection
Amitriptyline Elavil® Tricyclic Antidepressant / depression
Ketoconazole Nizoral® Anti-fungal / fungal infection
Imipramine Norfranil® Tricyclic Antidepressant / depression
Ritonavir Norvir® Protease inhibitor! HIV
Diphenhydramine Nytol® Antihistamine I Allergic rhinitis, insomnia
Nortriptyline Pamelor® Tricyclic Antidepressant / depression
Paroxetine Paxil® Anti-depressant I depression
Desipramine Pertofrane® Tricyclic Antidepressant! depression
Fluoxetine Prozac® Anti-depressant / depression
Galantamine Reminyl® Cholinesterase inhibitor! Dementia, Alzheimer’s
Fluoxetine Sarafem® Anti-depressant! depression
Doxepin Sinequan® Tricyclic Antidepressant I depression
Itraconazole Sporanox®Anti-fungal / fungal infection
Trimethoprim
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Sulfa Sulfa® Antibiotic! bacterial infection
Trimipramine Surmontil® Tricyclic Antidepressant / depression
muscarinic receptor
Solifenacin VESIcare® anatagonist
I treatment of overactive bladder
Protriptyline Vivactil® Tricyclic Antidepressant I depression
Sertraline Zoloft® Anti-depressant! depression
Escitalopram Cipralex® Anti-depressantJ Maor depression! Anxiety disorders
Dolasetron Anzemet® Anti-nausea I nausea, vomiting
Moxifloxacin Avelox® Antibiotic! bacterial infection
Nicardipine Cardene® Anti-hypertensive! high blood pressure
Fosphenytoin Cerebyx® Anti-convulsant! seizure
Clozapine Clozaril® Anti-psychotic /schizoprirenia
Perflutren lipid Definity® Imaging contrast agent! microspheres Echocardiography
Isradipine Dynacirc® Anti-hypertensive / high blood pressure
Venlafaxine Etfexor® Anti-depressant I depression
Lithium Eskalith® Anti-mania! bipolar disorder
Gemifloxacin Factive® Antibiotic! bacterial infection
Felbamate Felbatrol® Anti-convulsant! seizure
Ofloxacin Floxin® Antibiotic! bacterial infection
Foscarnet Foscavir® Anti-viral I HIV infection
Ziprasidone Geodon® Anti-psychotic/schizophrenia
Paliperidone Invega® Antipsychotic, atypical! Schizophrenia
Telithromycin Ketek® Antibiotic! bacterial infection
Granisetron Kytril® Anti-nausea! nausea and vomiting
Levofloxacin Levaquin® Antibiotic! bacterial infection
Vardenafil Levitra® phosphodiesterase inhibitor!
Vasodilator
Escitalopram Lexapro® Anti-depressantJ Ma or depression/ Anxiety disorders
Lithium Lithobid® Anti-mania! bipolar disorder
Indapamide Lozol® Diuretic! stimulate urine & salt loss
Dronedarone Multaq® Anti-arrhythmic! Atrial Fibrillation
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Chioral hydrate Noctec® Sedative! sedation/insomnia
Tamoxifen Nolvadex® Anti-cancer I breast cancer
Oxytocin Pitocin® Oxytocic! Labor stimulation
Tacrolimus Prograf® Immunosuppressant! Immune suppression
Ranolazine Ranexa® Anti-anginal/ chronic angina
Atazanavir Reyataz® Protease inhibitor! HIV
Chloroquine Aralen® Anti-malarial / malaria infection
Sotalol Betapace® Anti-arrhythmic I abnormal Females>Males heart rhythm
Clarithromycin Biaxin® Antibiotic! bacterial infection
Quinidine Cardioquin® Anti-arrhythmic I abnormal Females>Males heart rhythm
Amiodarone Cordarone® Anti-arrhythmic I abnormal Females>Males, TdP risk heart rhythm regarded as low
Ibutilide Corverf® Anti-arrhvthmic I abnormal Females>Males heart rhythm
Methadone Dolophine® Onapricaoteticagdoenpiesntdlepnacien control, Femates>Males Antibiotic;Gl stimulant /
Erythromycin E. ES® bacterial infection; increase Females>Males GI motility, Antibiotic; GI stimulant
Erythromycin Erythrocin® bacterial infection; increase Females>Males GI motility when given intravenously or at higher-than
Haloperidol Haldol® Anti-psychotic I recommended doses, risk schizophrenia, agitation of sudden death, QT prolongation
and torsades increases.
Halofantrine Halfan® Anti-malarial! malaria infection Females>Males
Astemizole Hismanal® Arhnintiihtiisstamine / Allergic No Longer available in U.S.
Droperidol lnapsine® Sedative;Anti-nausea I anesthesia adjunct, nausea
Probucol Lorelco® Antilipemic /1-lypercholesterolemia No longer available in U.S.
Thioridazine Mellaril® Anti-psychotic I schizophrenia
Methadone Methadose® Opiate agonist! pain control, Females>Males narcotic dependence
Domperidone Motilium® Anti-nausea! nausea Not available in the U.S.
Pentamidine NebuPent® Apnnetiu-minofencitaivel pneumocystis Females>Males
Disopyramide Norpace®Anti-arrhythmic! abnormal Females>Males heart rhythm
Pimozide Orap® tAicnsti-psychotic! Tourettes Females>Males
Levomethadyl Orlaam® Opiate agonist I pain control, narcotic dependence
Amiodarone Pacerone®Anti-arrhythmic! abnormal Females>Males,TdP risk heart rhythm regarded as low
Pentamidine Pentam® Apnnetiu-minofencitaive / pneumocystis Females>Males
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Procainamide Procan® Anti-arrhvthmic / abnormal heart rhythm
Procainamide Pronestyl® Anti-arrhythmic I abnormal heart rhythm
Cisapride Propulsid® GI stimulant? heartburn Restricted availability; Females>Males.
Quinidine Quinaglute®Anti-arrhythmic/ abnormal Females>Males heart rhythm
Terfenadine Seldane® Antihistamine
I Allergic No longer available in U.S. rhinitis
Mesoridazine Serentil® Anti-psychotic? schizophrenia
Chiorpromazine Thorazine® Anti-psychotic? Anti-emetic ?schizophrenia) nausea
Dofetilide Tikosyn® Anti-arrhythmic I abnormal heart rhythm
Arsenic trioxide Trisenox® Anti-cancer / Leukemia
Bepridil Vascor® Anti-anginal I heart pain Females>Males
Sparfioxacin Zagam® Antibiotic? bacterial infection
APPENDIX III: DRUGS THAT INDUCE CYP3A4
CYP3A4 inducers which are considered to be clinically relevant are: carbamazepine, phenobarbital,
phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone Avasimibe, Bosentan, efavirenz,
etravirine, modafinil, nafcillin, Amprenavir, aprepitant, armodaflnil, echinacea, pioglitazone, prednisone,
rufinamide
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