A Randomized, Placebo-Controlled Study of Liraglutide 3mg Daily (Saxenda®) in Obese or Overweight Patients With Stable Bipolar Disorder
Phase: PHASE2
Conditions: Bipolar Disorder, Obesity
Sponsor: Lindner Center of HOPE

Protocol Title
A Randomized, Placebo-Controlled Study of Liraglutide 3mg daily (Saxenda®) in Obese or Overweight
Patients with Stable Bipolar Disorder
INVESTIGATOR-INITIATED STUDY PROPOSAL
UNIVERSAL TRIAL NUMBER (UTN)
U1111-1175-0805
Susan L. McElroy, MD
Research Institute
Lindner Center of HOPE and
University of Cincinnati Department of Psychiatry & Behavioral Neuroscience
4075 Old Western Row Road
Mason, Ohio 45040
Correspondence to:
Susan L. McElroy, MD
Chief Research Officer
Lindner Center of HOPE
4075 Old Western Row Road
Mason, Ohio 45040
Phone: (513) 536-0700
Fax: (513) 536-0709
Email: susan.mcelroy@lindnercenter.org
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BACKGROUND AND SIGNIFICANCE:
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Obesity is common among persons with severe mental illness (SMI), especially those with bipolar
3
disorder (BP) (1-5). It is estimated that 45-55% of people with SMI are obese, making obesity 1.5-2 times
4
more common among those with SMI than among the general population (6). Indeed, in a recent
5
pragmatic lithium trial conducted in BP, 69% of the subjects were overweight or obese (7). Although 6
the precise mechanism underlying the relationship between obesity and SMI is unknown, it is thought to
7
be multifactorial, involving genetic factors, intrinsic features of SMI (e.g., overeating, poor dietary
8
choices, sedentary lifestyle, and sleep dysregulation), and the weight-gaining effects of most of the
9
psychotropic medication used to treat SMI (1-4, 6, 8-10)
10
11
Importantly, obesity is thought to contribute to the well-documented elevated mortality from
12
cardiovascular disease (CVD) among those with BP (11-15). Thus, weight reduction in obese people with
13
BP might be important for reducing their morbidity and mortality from CVD and other obesity-related
14
conditions (e.g., diabetes and metabolic syndrome). Conversely, the presence of obesity in patients with
15
BP is associated with a more severe course of illness (16, 17), a lower health-related quality of life (18), 16
reductions in brain gray and white volumes (19, 20), and non-adherence with antipsychotic medications 17
(21). Indeed, it has been hypothesized that successful treatment of obesity in those with BP might benefit
18
mental as well as physical health (17). It is thus imperative that obesity be a focus of treatment in those 19
with BP.
20
21
Comprehensive behavioral weight management programs have shown some effectiveness for obesity in 22
patients with SMI, but the weight loss is modest at best and such programs are difficult to implement and
23
not widely available (22-25). Several medications have been shown to mitigate psychotropic-induced
24
weight gain, particularly metformin and topiramate, but many patients either do not respond to these
25
agents or are unable to tolerate them (2). Importantly, the efficacy and safety of newly available weight-
26
loss agents have not been evaluated in people with SMI.
27
28
In December 2014, the U.S. Food and Drug Administration approved liraglutide [rDNA origin] 3 mg/day
29
subcutaneous [sc] injection) (Saxenda®) as a treatment option for chronic weight management in
30
individuals with obesity (26-32). The drug is approved for use in adults with a body mass index (BMI) of
31
30 or greater (obesity) or adults with a BMI of 27 or greater (overweight) who have at least one weight-
32
related comorbid condition such as hypertension, type 2 diabetes, or dyslipidemia (33). Liraglutide is a
33
glucagon-like peptide-1 (GLP-1) receptor agonist. Saxenda® and Victoza® contain the same active
34
ingredient (liraglutide) at different doses (3 mg and 1.8 mg, respectively). However, unlike Victoza®,
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Saxenda® is not indicated for the treatment of type 2 diabetes, as the safety and efficacy of Saxenda® for
36
the treatment of diabetes has not been established.
37
38
Several lines of evidence suggest that liraglutide 3.0 mg sc injection (Saxenda®), in combination with a
39
reduced-calorie diet and increased physical activity, would be a useful weight-loss treatment for patients
40
with BP who are overweight or obese.
41
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First, GLP-1 is a gut/brain peptide that is secreted from intestinal mucosal enteroendocrine L cells in
43
response and in proportion to nutrient stimulation of the gut, and that suppresses food intake by acting on
44
receptors in key areas of the brain that regulate energy balance (e.g., hypothalamus and hindbrain) (34-
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37). In humans, administration of GLP-1 reduces food intake and increases satiation in a dose-dependent
46
manner (37). Obesity in people with BP, as well as psychotropic-induced weight gain, are thought to be
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due to in part to increased food intake (2). It is thus possible that liraglutide 3.0 mg sc injection will
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decrease food intake in obese patients with BP, thereby reducing body weight.
49
50
Second, preliminary preclinical and clinical findings suggest liraglutide 3.0 mg sc injection may be
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effective for antipsychotic-induced weight gain and antipsychotic-induced obesity (38). Thus, liraglutide
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has been shown to produce weight loss in animal models of olanzapine-induced weight gain (39, 40). In
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one of these studies, liraglutide also produced antidepressant-like effects (40). (Indeed, other animal
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studies suggest that liraglutide may have antipsychotic properties (41).) In the only published case of
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liraglutide use in a patient with SMI, an obese (BMI 33.5=mg/kg2) 60-year-old woman with
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schizophrenia treated with clozapine, liraglutide (1.8mg/day) produced a sustained weight loss of 7.7 kg 57
(an 8.7% body weight reduction) over two years (42). Liraglutide was well tolerated and there were no 58
psychiatric adverse events (i.e., the patient’s schizophrenia remained stable). At our own center, we have
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treated a 32-year-old woman with schizoaffective disorder, bipolar type and obesity (BMI=36 mg/kg2)
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receiving one depot and two oral antipsychotics with liraglutide 3.0 mg sc injection and, to date, she has
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lost 7.5 kg (an 8.3% body weight reduction) over a 4-month period. She reports the liraglutide 3.0 mg sc
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injection has reduced her hunger and improved her satiety. She has tolerated liraglutide 3.0 mg sc
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injection well and has had no difficulties with giving herself the injections, her psychological symptoms
64
have remained stable, and there have been no adverse psychiatric effects. Indeed, her mild tardive
65
dyskinesia is much improved
66
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Third, relative to other weight loss agents, liraglutide 3.0 mg sc injection has a favorable psychiatric and 68
cardiovascular adverse event profile (43, 44). Regarding psychiatric events, in the pivotal liraglutide 3.0
69
mg sc injection clinical trials, 6 (0.2%) of 3384 liraglutide 3.0 mg sc injection-treated patients had suicidal
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ideation (one of these individuals made a suicide attempt) compared with none of the 1941 placebo-
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treated patients (33). Additionally, 2.4% of liraglutide 3.0 mg sc injection recipients had insomnia and
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2.0% had anxiety, compared with 1.7% and 1.6 %, respectively, of placebo recipients. Conversely,
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lorcaserin (Belviq®) was associated with euphoria (0.2% vs < 0.1% for placebo) and is contraindicated in
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patient’s receiving serotonergic medications (and many psychotropics enhance serotonin function) (45). 75
Phenermine/topiramate combination (Qsymia®), at the highest approved dose, was associated with
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insomnia (11.1% vs 5.8% for placebo), depression/mood problems (7.6% vs 3.4% for placebo), and
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anxiety (7.9% vs 2.6% for placebo) (46). Additionally, one of the components of Qsymia®, topiramate, is 78
associated with suicidality. Bupropion/naltrexone combination (Contrave®), at the highest recommended 79
dose, was associated insomnia (9.2% vs 5.9% for placebo), anxiety (4.2% vs 2.8% for placebo), and
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irritability (2.6% vs 1.8% for placebo) (47). Moreover, there are reports of components of these latter
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medications (e.g., phentermine and bupropion) causing severe adverse psychiatric events, such as mania
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and psychosis (48-52). Taken together, these findings suggest that liraglutide 3.0 mg sc injection may be
83
the least likely of these weight management medications to exacerbate psychiatric symptoms in people 84
with BP. Indeed, GLP-1 analogues have been reported to produce enhanced well-being in patients with
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diabetes (53).
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Taken together these data support the hypothesis that liraglutide 3.0 mg sc injection will reduce body
88
weight and improve metabolic variables in obese or overweight patients with BP without worsening 89
psychiatric symptoms. We predict that liraglutide 3.0 mg sc injection will display greater efficacy as
90
compared to placebo in decreasing body weight in patients with BP who are obese or overweight. To
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prove this hypothesis, we will conduct a single-center, randomized, placebo-controlled, double-blind,
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parallel-group, 2-arm clinical trial of liraglutide 3.0 mg sc injection in 60 obese or overweight outpatients
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with stable BP. We have chosen BP rather than another SMI because it is the most common SMI (more
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common than schizophrenia or schizoaffective disorder) and has a particularly strong association with 95
obesity.
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SPECIFIC OBJECTIVES:
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Primary Objective:
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The primary objective of this study is to evaluate the efficacy of liraglutide 3.0 mg sc injection (in
100
combination with a reduced calorie diet and increased physical activity) compared with placebo for
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reducing body weight in obese or overweight adults with stable BP, as measured by percent change in
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body weight.
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Secondary Objectives:
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Secondary objectives are:
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- To evaluate the efficacy of liraglutide 3.0 mg sc injection as measured by:
107                                            - Proportion of participants who have a ≥ 5% loss in body weight
108                                            - Body weight (kg)
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- BMI
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- Waist circumference
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- Fasting lipids
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- Fasting glucose
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- HgA1c levels
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- Three-Factor Eating Questionnaire (TFEQ) (54)
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- Binge Eating Scale (BES) (55)
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- To evaluate the safety and tolerability of liraglutide 3.0 mg sc injection, using:
117                                            - Mental status examinations
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- Young Mania Rating Scale (YMRS) (56)
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- Montgomery Asberg Depression Rating Scale (MADRS) (57)
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- Clinical Global Impressive Scale for modified Bipolar Disorder (CGI-BP) (58)
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- Physical examinations
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- Vital signs
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- 12-lead electrocardiograms (ECG)
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- Clinical laboratory tests
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- Adverse event reports
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- Columbia-Suicide Severity Rating Scale (C-SSRS) (59)
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RESEARCH DESIGN AND METHODS
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Study hypothesis (es):
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The central research question is whether liraglutide 3.0 mg sc injection is efficacious for reducing body
132
weight in obese or overweight patients with BP. We hypothesize that liraglutide 3.0 mg sc injection will
133
be an efficacious, safe, and well tolerated treatment for weight loss in obese or overweight patients with
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stable BP. We predict that liraglutide 3.0 mg sc injection will display greater efficacy as compared to 135
placebo in decreasing body weight in patients with BP who are overweight or obese without increasing
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psychiatric adverse events. We also predict that liraglutide 3.0 mg sc injection will produce a greater
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percentage of patients who lose ≥ 5% of baseline body weight, and improve BMI, waist circumference,
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fasting lipid and glucose levels, HgA1c levels, and measures of eating psychopathology.
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Endpoints:
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The primary endpoint will be the percent change in body weight from Baseline (Week 0) to week
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40/Early Termination (ET) (see Table 1 for a schedule of assessments). Secondary endpoints will include
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proportion of participants who lose ≥ 5% of baseline body weight, and change from baseline in body
144
weight (kg), BMI, waist circumference, and metabolic variables (fasting lipids and glucose, and HgA1c
145
levels). Exploratory secondary endpoints will be change from baseline in eating psychopathology,
146
assessed with the Three Factor Eating Questionnaire (TFEQ) (54) and Binge Eating Scale (BES) (55). 147
Safety endpoints assessed at each study visit will be mental status examination, clinically-administered 148
scales that assess psychopathology (CGI-BP scale [both Severity and Improvement subscales], YMRS, 149
MADRS, and CSSRS), vital signs, and adverse events determined by clinical interview. Laboratory tests
150
and 12-lead electrocardiograms (ECGs) will be obtained at Screening, week 8, week 16/ET, and week 151
40/ET. Compliance will be assessed at each visit with inspection of returned multi-dose pens. Potential
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interactions between liraglutide and psychiatric medications will be monitored and recorded on the
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Potential Drug Interaction form (see p. 28).
154
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Study type:
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This is a single-center, randomized, placebo-controlled, double-blind, two-arm, parallel-group, fixed-dose
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efficacy and safety study with 3 phases: a 3-27 day Screening period; a 40-week randomized, double-
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blind Treatment period (4 weeks of dose titration and 36 weeks of dose maintenance); and a 1-week 159
Follow-up (drug discontinuation) period. The purpose of the 40-week Blinded Treatment phase is to
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establish the efficacy of liraglutide 3.0 mg sc injection for weight loss in obese patients with stable BP.
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Study population:
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We expect to screen about 90 subjects in order to randomize 60 subjects in a 1:1 ratio to drug or placebo.
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Patients will be recruited from the Lindner Center of HOPE, Mason, OH, a University of Cincinnati
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College of Medicine Affiliate. Patients will be recruited by clinician referral and advertisement.
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Participants will include 60 outpatients with a DSM-IV (60) diagnosis of BP that is stable, who are obese
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or overweight with at least one weight-related comorbidity, and who have been receiving a stable
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psychotropic regimen for the past three months. The weight-related comorbidities to be included will be
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hypertension, type 2 diabetes, and dyslipidemia. Allowed psychotropic medications for BP will include
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mood stabilizers (lithium, valproate, and lamotrigine), antipsychotics (asenapine, aripiprazole,
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cariprazine, chlorpromazine, clozapine, haloperidol, loxapine, olanzapine, paliperidone, perphenazine,
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quetiapine, resperidone, thiothixene, trifluoperazine, or ziprasidone), antidepressants, and anxiolytics
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(benzodiazepines, gabapentin or pregabalin, and buspirone). Stable BP will be operationally defined as a
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CGI-BP-Severity score of 1through 3 (1= normal, not at all; 2= borderline mentally ill; 3=mildly ill); a 176
YMRS score ≤12; a MADRS score ≤19, and the absence of clinically significant suicidality and
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psychosis. Participants must be 18 through 65 years of age, be able to provide informed consent, and if
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female, be postmenopausal, surgically incapable of childbearing, or practicing a medically acceptable
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method(s) of contraception (e.g., hormonal method, intrauterine device) for at least 1 month prior to study
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entry and throughout the study. Exclusion criteria include subjects with a lifetime DSM-IV Axis I
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diagnosis of dementia, a psychotic or depressive disorder, or a sub
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stance use disorder within the past three months; those with clinically significant psychotic features or 183
suicidal ideation; those with serious or unstable general medical illnesses; those with a personal or family
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history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2; those who are
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allergic to or who have demonstrated hypersensitivity to liraglutide 3.0 mg sc injection or any of its
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components; and females who are pregnant, nursing, or intend to become pregnant. Specific entry criteria
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are listed below.
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Inclusion Criteria: Criteria for entering this study will include all of the following:
190               1. Men and women, ages of 18-65 years, inclusive.
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2. Participants will have a DSM-IV bipolar disorder that is clinically stable.
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3. Participants will have received a stable major psychotropic drug regimen (except for minor dosage
193                      adjustments) for at least 3 months prior study entry. Major psychotropic drugs are antipsychotics,
194                      mood stabilizers, and antidepressants. Subjects may have had changes in adjunctive
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benzodiazepines and hypnotic agents.
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4. Participants will be obese (defined as a BMI ≥ 30 mg/kg2) or overweight (defined as BMI ≥ 27
197                      kg/m2) with at least one weight-related comorbidity, such as hypertension, type 2 diabetes, or
198                      dyslipidemia.
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5
Participants in treatment for a weight-related comorbidity (hypertension, type 2 diabetes, and/or
200                      dyslipidemia) must be on a stable and allowed treatment regimen for that condition for at least 3
201                      months prior to study enrollment.
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6 Participants will be able to provide informed consent before any trial-related activities.
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Exclusion Criteria: Criteria for exclusion from this study will include any of the following:
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1. Women who are pregnant, lactating, or of childbearing potential who are not using adequate
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contraceptive measures. The following are considered to be adequate methods of birth control: 1.
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Intrauterine device (IUD); 2. Barrier protection; 3. Contraceptive implantation system (Norplant);
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4. Oral contraceptive pills; 5. A surgically sterile partner; and 6. Abstinence. Women who are > 2
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years post-menopausal or surgically-sterile are not considered of childbearing potential. All
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female participants will have a negative pregnancy test prior to randomization.
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2. Participants who have made a suicide attempt in the last 10 years, who are displaying clinically
212                      significant psychotic features, suicidality, or homicidality on mental status examination, or who
213                      have suicidal ideation or behavior as assessed with the C-SSRS.
214
3. Participants who are receiving behavioral weight loss treatment (BWLT) (e.g., Weight Watchers)
215                      that was begun within the 3 months before study entry. Participants who are receiving BWLT that
216                      was started 3 months prior to the beginning of the study will be allowed to continue to receive
217
their BWLT during the trial only if they have had no weight loss in the past 3 months and they 218
agree to not make any changes in the frequency or nature of their BWLT during the course of the
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drug trial.
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4. A DSM-IV diagnosis of a substance-related or addictive disorder (except a tobacco-related
221                      disorder) within the 3 months prior to enrollment.
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5. A DSM-IV diagnosis of dementia, a psychotic disorder, or a depressive disorder.
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6. History of any psychiatric disorder which might interfere with a diagnostic assessment, treatment,
224                      or compliance.
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7. Clinically unstable medical disease, including cardiovascular, hepatic, renal, gastrointestinal,
226                      pulmonary, neurological, metabolic, endocrine, or other systemic disease. Clinically stable
227                      hypertension, type 2 diabetes, or dyslipidemia are not exclusionary.
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8. Have a history of a structural cardiac abnormality, valvular cardiac disease, cardiomyopathy,
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serious heart rhythm abnormality, coronary artery disease, congestive heart failure, stroke, or other
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serious cardiovascular problem.
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9. Have an ECG with significant arrhythmias or conduction abnormalities, which in the opinion of
232                      the physician investigator preclude study participation.
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10. Have clinically relevant abnormal laboratory results.
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11. Participants requiring treatment with any drug which might interact adversely with or obscure the
235                      action of the study medication. This includes anti-obesity drugs, psychostimulants, modafinil or 236
armodafinil, and topiramate or zonisamide. Participants receiving metformin at a stable dose for ≥ 237
3 months can be included.
238
12. Participants receiving GLP-1 based therapies, sodium-glucose co-transporter 2 inhibitors
239                      (SGLT2s), thiazolidinediones, sulfonylureas, or insulin.
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13. Participants with a personal or family history of medullary thyroid carcinoma or Multiple
241                      Endocrine Neoplasia syndrome type 2.
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14. Participants who have received any investigational medication within three months prior to
243                      randomization.
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15. Participants previously screen-failed or randomised to participate in this trial.
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16. Participants who have a known or suspected allergy to liraglutide 3.0 mg sc injection, its
246                      constituents, or related products.
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17. Participants with a urine drug screen positive for a drug that, in the opinion of the investigator, is
248                      being abused.
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18. Participants with a past medical history of pancreatitis.
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19. Participants who had received any investigational drug within 3 months prior to this trial.
251
20. Participants who require bariatric surgery or are anticipated to require it during the course of the
252                      trial. If such surgery becomes warranted during the study, such patients will be excluded from the
253                      primary endpoint analysis.
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Withdrawal Criteria:
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Participants may withdraw at will from the study at any time. Participants will be withdrawn in the event
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of pregnancy or intention to become pregnant. Additionally, participants will be discontinued if they
261
display: clinically significant suicidality, defined as a YES to item 1 of the C-SSRS or a C-SSRS-defined
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suicide attempt; a YMRS score >12 (indicating at least moderately ill manic symptoms); a MADRS score
263
>19 (indicating at least moderately severe depressive symptoms); a CGI-I-BP-Severity score of much or
264
very much worsened; or clinically significant suicidal ideation or psychotic symptoms on mental status 265
examination. In the absence of the above, participants will be terminated at the treating psychiatrist’s
266
discretion in response to symptoms of sufficient severity that a new psychiatric medication needs to be 267
added (dosage changes in ongoing psychotropics will be permitted). The Investigator may also withdraw
268
participants for lack of compliance with study procedures if she or the research team has any concerns for
269
the participant’s safety. Upon termination for any of these reasons, patients will receive care judged
270
appropriate by the treating investigators including, if needed, referral for emergency care.
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Participant compliance with dosing requirements will be monitored with pen inspection. Participants
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displaying non-compliant behaviors with study medication administration and accountability (such as
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taking more medication than prescribed, losing pens, or failure to return pens to clinic) will be re-
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educated. .
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Subject Replacement:
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Subjects will not be replaced if they withdraw or become ineligible at any time after the Baseline visit.
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Rational for study population:
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Approximately half of persons with BP are obese, yet no medication is regularly used (or indicated) for
282
weight loss in this population, signifying a large unmet medical need. Data showing that a weight loss
283
drug is beneficial in obese persons with BP would be a significant advancement to the medical field. 284
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Visit Procedures:
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During Screening, patients will be evaluated for eligibility. During the 40-week Blinded Treatment
287
period, patients will be scheduled for weekly visits for the first 4 weeks of treatment (dose titration, Visit
288
0 through Visit 4), every other week for 12 weeks (dose maintenance, Visits 5 through 10), and then every
289
4 weeks for 24 weeks (continued dose maintenance, Visits 11-16) for assessments and study medication 290
dispensation. After randomization to liraglutide 3.0 mg sc injection or placebo, patients will be permitted
291
to have dosage changes in their major psychotropic medications (antipsychotics, mood stabilizers, and
292
antidepressants), and such changes will be recorded on the concomitant medication form. Addition of
293
these psychotropic medications will also be permitted and these medications will be recorded on the
294
concomitant medication form.
295
296
All participants will be offered nutritional and lifestyle modification counseling following the 2015-2020
297
Dietary Guidelines for Americans (http://health.gov/dietaryguidelines/2015/guidelines/?linkId=20169028)
298
at Baseline (Visit 0), Visit 4, Visit 6, Visit 8, and Visits 10-15.
299
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Study medication will be supplied in pre-filled, multi-dose pens that can deliver the following doses
301
subcutaneously: 0.6mg, 1.2mg, 1.8mg, 2.4mg, and 3mg. At the beginning of the Blinded Treatment
302
period, the dosage of liraglutide will be 0.6 mg/day. Study drug dosage will be increased to 1.2mg/day on
303
day 7 (Visit 1). In the following 3 weeks, the dose will be increased to 1.8mg/day (day 14, Visit 2),
304
2.4mg/day (day 21, Visit 3), and then to the target dose of 3mg/day (day 28, Visit 4), respectively. If
305
patients do not tolerate an increased dose during dose escalation, the dose escalation can be delayed for
306
approximately one additional week. The study medication dose (3 mg/day) will remain unchanged 307
during the final 36 weeks of the Blinded Treatment Phase.
308
309
Study drug will be discontinued upon completion of the 40-week Blinded Treatment period (Visit 16) or
310
if the subject terminates the study earlier (early termination, ET). The follow-up period begins upon
311
completion of Visit 16 (week 40), ET (depending upon when the subject completes their study
312
participation), and concludes with a follow-up visit (Visit 17) which occurs 7 days after Visit 16, or ET. 313
Follow-up assessments include adverse events, concomitant medication form, potential drug interaction
314
form, and termination record.
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Listed below are the specific procedures to be done at each study visit.
317
318
Pretreatment Period Screening Visit (s):
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The Screening period will be a minimum of 3 days and maximum of 28 days and be used to evaluate 320
study candidates for inclusion and allow for wash-out of disallowed medications. At the first Screening
321
visit (Visit -1), informed consent will be obtained. Sections A, B, and C of the Structured Clinical
322
Interview for DSM-IV (SCID) (61) will be performed to establish that the patient meets DSM-IV criteria
323
for BP. A mental status examination, YMRS, MADRS, and CGI-BP-Severity Scale will be performed to
324
establish the severity of psychiatric symptoms. Medical history will be reviewed, a physical exam
325
performed, and laboratory studies (complete metabolic profile with fasting glucose and lipids, CBC with
326
diff and platelets, liver function tests, renal function tests, electrolytes, HgA1c level, and urinalysis) and 327
ECG will be obtained. Patients’ mental health providers will be consulted about their suitability for study
328
participation. Based on these evaluations, it will be determined whether participants meet entry criteria; 329
participants meeting these criteria will continue in the screening process. The patient will not receive any
330
disallowed medications during this period.
331
332
Patient screening requires:
333
1. Informed consent
334
2. Psychiatric evaluation and the Structured Clinical Interview for DSM-IV (61) to confirm the
335                      diagnosis of BP by DSM-IV criteria and evaluate protocol-specified subject selection
336
requirements
337
3. Mental status examination
338
4. Medical History and physical eexamination (including vital signs, height, weight, and BMI
339                      determination)
340
5. Fasting blood draw for laboratory tests including serum β-HCG, CBC, TSH, liver and renal
341
panels, electrolytes, lipid profile, glucose, and HgA1C level. Of note, we have approved language
342
from the University of Cincinnati IRB for use during the initial phone screen that allows us to
343
instruct subjects to fast before they come to the Screening visit and sign informed consent. The
344
phone screen form with the IRB-approved language is now listed on page 21(lines 908-915). 345
6. 12-lead Electrocardiogram (ECG)
346
7. Urinalysis and urine drug screen
347
8. YMRS
348
9. MADRS
349
10. CGI-BP-Severity Scale
350
11. C-SSRS lifetime version
351
12. Concomitant medication form
352
13. Adverse event form
353
14. Drug interaction form
354
355
Baseline Visit (Visit 0):
356
At Baseline, subjects meeting all of the inclusion/exclusion requirements will be randomized to drug or
357
placebo in a 1:1 ratio. The baseline evaluation will consist of:
358
1. Inclusion/Exclusion Criteria checklist
359
2. Mental status examination
360
3. Vital signs, weight, waist circumference, and determine BMI
361
4. YMRS
362
5. MADRS
363
6. CGI-BP-Severity and -Improvement Scales
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7. C-SSRS-since last visit
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8. Urine pregnancy test
366
9. Three Factor Eating Inventory (TFEQ) (55)
367
10. Binge Eating Scale (BES) (54)
368
11. Concomitant medication form
369
12. Adverse events form
370
13. Potential drug interaction form
371
14. Counseling for reducing diet and increasing physical activity
372
373
Upon determination of continued eligibility, a subject identification number will be assigned and a
374
prefilled dial-a-dose injection pen containing liraglutide or matching placebo will be dispensed along with
375
instructions for its use. The first injection of study medication will be done at the end of the visit with
376
guidance from the research team. The same rater will evaluate the subject throughout the study.
377
378
Blinded Treatment Period: Baseline Visit (Visit 0) Through Week 16 (Visit 40) or Early
379
Termination (ET):
380
During the 40-week Blinded Treatment period, patients will be scheduled for weekly visits for the first 4
381
weeks of treatment (dose titration; Visits 0 through Visit 4), every other week for the next 12 weeks
382
(dose-maintenance; Visits 5 through 10), and then every 4 weeks for the next 24 weeks (continued dose
383
maintenance; Visits 11 through 16) for assessments and dispensation of study medication. At each visit
384
from Baseline (Visit 0) through Visit 16, the participant will be evaluated for weight, vital signs, mental
385
status examination, psychiatric symptoms, concomitant medications, adverse events, and potential drug
386
interactions.
387
388
During the Treatment period, items 2-7, 8 and 11-14 from the Baseline evaluation will be repeated at each 389
scheduled visit and at ET visits (see Table 1). In addition, items 9 and 10 will be repeated at Visits 4, 6, 8, 390
and 10-16/ET. Laboratory tests, ECG, and urinalysis will be repeated at Visits 6, 10, and 16. Urine
391
pregnancy tests will be performed at every visit (Visits 0-16/ET). Used and unused study medication and
392
packaging will be collected and drug accountability assessed at every visit. Every effort will be made to
393
keep the participant on the original time-frame for scheduled visits. If the participant deviates from this
394
schedule, every effort will be made to return him/her to the original schedule of visits.
395
396
Participants will be instructed to bring their used and unused study medication and packaging to every
397
visit. Participant compliance and drug accountability will be assessed by the investigator at every
398
treatment phase visit by individual pen inspection and entered on the drug accountability log. Participants
399
taking 80-100% of prescribed study medication will be considered compliant.
400
401
Final Treatment Phase Evaluation (Week 40 or ET):
402
Study drug will be discontinued upon completion of the Blinded Treatment phase (Week 40; Visit 16) or
403
if the participant terminates the study earlier (early termination, ET).
404
405
The following evaluations will be conducted at the final treatment evaluation:
406
407
1. Mental status examination
408
2. Obtain vital signs, weight, waist circumference, and determine BMI.
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3. Obtain YMRS, MADRS, CGI-BP-Severity and -Improvement Scales, and C-SSRS since last visit
410                      version.
411
4. Perform physical examination.
412
5. Obtain laboratories (complete metabolic profile, CBC with diff + platelets, urinalysis, fasting
413                      lipids and glucose, and HgA1c level).
414
6. Repeat ECG.
415
7. Assess and record adverse events
416
8. Drug interaction form
417
9. Record concomitant medication use.
418
10. Assess study drug accountability.
419
420
Final (Follow-Up) Visit Evaluation (Visit 17):
421
The follow-up period begins upon completion of Visit 16 or ET visit and concludes with a follow-up visit
422
(Visit 17) which occurs 7 days thereafter. Follow-up includes assessment of psychiatric symptoms,
423
adverse events, potential drug interactions, and termination record.
424
425
1. Mental status examination
426
2. YMRS, MADRS, CGI-BP-Severity and –Improvement, and C-SSRS since last visit version
427
3. Vital signs and weight
428
4. Urine pregnancy test
429
5. Assess and record adverse events
430
6. Potential drug interaction form
431
7. Termination record
432
433
Assessments for Efficacy
434
The primary efficacy measure will be the percent change in body weight from Baseline to Week 40/Early
435
Termination. Weight will be measured in kg and obtained on the same scale, zeroed at each use, and with
436
the subject in light clothing and no shoes. Secondary efficacy variables will be proportion of patients who
437
have ≥ 5% reduction in body weight, and changes in body weight (kg), BMI, waist circumference, and
438
measures of metabolic variables (fasting lipids and glucose, and HgA1C).
439
440
Assessments for Safety
441
The investigator will conduct and record a medical history at the Screening Visit, including a medication
442
history and all clinically relevant information in conjunction with a Physical Examination. Any
443
abnormalities in the review of systems and exam will be noted in the source documents.
444
445
The following assessments will be used to assess safety at each visit: vital signs, taken after the
446
participant is rested and seated for 5 minutes, mental status examination, YMRS, MADRS, CGI-BP-
447
Severity and -Improvement Scales, C-SSRS, urine pregnancy test, concomitant medication form, adverse
448
events, drug interaction form, and study drug accountability. All adverse events will be evaluated as
449
potential drug interactions for those medications used to treat BP (mood stabilizers, antipsychotics,
450
antidepressants, anxiolytics, and sedative-hypnotics) with the drug interaction form. A drug interaction is
451
defined as an AE that is possibly due to an interaction between study drug and a BP medication a subject
452
is receiving.
453
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The YMRS (56) is a widely used, validated, and reliable clinician-administrated instrument that assesses
455
the severity of the symptoms of mania. It consists of 11 items rated on a scale of 0 to 4 (items 1-4, 7, 10,
456
and 11) or 0 to 8 (items 5, 6, 8, and 9) (total score range 0 to 60), with 0 being the absence of symptoms
457
and higher scores representing greater severity of manic symptoms. The total thus ranges from 0 (no
458
symptoms) to 60 (extremely severe symptoms). A mild level of symptoms corresponds to a score of ≤ 12.
459
460
The MADRS (57) is a widely used, validated, and reliable clinician-administered measure of depressive
461
symptoms. It consists of 10 items, with each item yielding a score of 0 to 6 (total score range 0 to 60). 462
Higher scores indicate more severe depressive symptoms. Usual cutoff points are: normal is 0 to 6; mild
463
depression is 7 to 19, moderate depression is 20 to 34; and >34 is severe depression.
464
465
The Clinical Global Severity item of the CGI-BP (CGI-BP-S) consists of seven ordered categories that
466
describe the global severity of the patient’s BP (58). The categories (and the integer values assigned to
467
them) for the purpose of analyses are: normal, not at all ill (1), borderline mentally ill (2), mildly ill (3),
468
moderately ill (4), markedly ill (5), severely ill (6), and among the most extremely ill (7). The Clinical
469
Global Improvement item of the CGI-BP (CGI-BP-I)consists of seven, ordered categories that describe
470
the patient’s global condition compared with baseline (58). The categories (and the integer values
471
assigned to them for the purpose of analyses) are as follows: very much improved (1), much improved
472
(2), minimally improved (3), no change (4), minimally worse (5), much worse (6), and very much worse
473
(7).
474
475
The C-SSRS is a summary measure of suicidality, assessing both suicidal behavior and ideation, and has
476
been used at the National Institute of Mental Health and in multi-site industry trials nationally and
477
internationally in a range of therapeutic areas and indications (59).
478
479
Regarding adverse event evaluation, participants will be asked if they have experienced any unusual or
480
unwanted symptoms at each visit (none will be suggested, and adverse experiences will be classified and
481
grouped by body system, using a coding system based on the National Adverse Drug Reaction Directory
482
[COSTART]). Adverse events will be recorded on the adverse event form. All adverse events will be
483
evaluated as potential drug interactions with those medications the subject is receiving for treatment of his
484
or her BP (mood stabilizers, antipsychotics, antidepressants, anxiolytics, and sedative-hypnotics) with the
485
drug interaction form. Potential drug interactions will be recorded on the drug interaction form. Other
486
safety evaluations, all done at Screening and Visits 16/ET, will be: physical examination; routine
487
laboratory evaluations, including hematology, serum chemistry, and urinalysis; and an ECG. The
488
interpretation of ECG results will follow the categories “normal”, “abnormal”, “not clinically significant”
489
or “abnormal, clinically significant” and only “normal” and “abnormal, not clinically significant” results
490
will be allowed at Baseline. Urine pregnancy tests will be performed at every visit post Baseline.
491
Abnormal clinical laboratory or physical exam results will be clinically evaluated to determine if
492
intervention is warranted.
493
494
Other Assessments:
495
The TFEQ is a reliable and validated self-report measure of three domains of eating behavior often 496
deranged in people with obesity: hunger, disinhibition over eating, and cognitive restraint over eating
497
(54). The BES is a valid and reliable self-report scale that assesses the presence and severity of binge
498
eating symptoms (55).
499
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Subject Compliance
501
Subjects are instructed to bring their unused study medication and packaging to every visit. Subject
502
compliance and drug accountability will be assessed by the investigator at every treatment phase visit by
503
individual pens inspection and entered on the drug accountability log. Compliance will be assessed at 504
each visit with inspection of returned multi-dose pens. Subjects taking 80-100% of prescribed study
505
medication will be considered compliant.
506
507
508
STATISTICAL CONSIDERATIONS:
509
Sample Size Calculation
510
The power analysis for this study uses a two-sample t-test on the mean weight change from baseline to
511
week 40 (or endpoint for patients who discontinue prematurely) in the two treatment groups in the
512
modified intent-to-treatment (ITT) sample. This sample will consist of all study participants who: 1) were
513
randomized, 2) received at least one study medication dosage, and 3) had at least one post-baseline
514
efficacy assessment. We expect a 5% attrition rate from baseline to week 1. We therefore expect the
515
proposed sample size of 60 to give an ITT sample of 56. Using this ITT sample size, along with a
516
significance level of 0.05 and power of 0.80, we will be able to detect effect sizes as small as 0.76.
517
518
This effect size corresponds to a 4.5 kg greater weight reduction in the liraglutide group vs. the placebo
519
group. The 4.5 kg reduction was calculated (0.76 x 6.0) using an expected standard deviation (SD) of 6.0
520
kg based on Wadden et al. (SD=7.0 at 56 weeks) and Astrup et al. (SD=5.6 for power analysis). This is a
521
clinically meaningful difference, especially in this population, where many patients are taking
522
antipsychotics, which are associated with weight gain. We expect our primary analysis (longitudinal
523
mixed model) to have more power due to the repeated visit data for each subject (60 subjects x 16 524
treatment period visits = 960 maximum number of observations).
525
526
Statistical Methods
527
Chi-square, Fisher’s Exact, Wilcoxon rank sum or two-sample t-tests will be used to examine statistical
528
differences between the placebo and drug condition on baseline characteristics and categorical outcome
529
measures. The primary analyses will be longitudinal data analyses (LDA) using PROC MIXED (SAS,
530
Cary N.C. U.S.A.). LDA will model the mean change in the primary and secondary outcome measures,
531
over the treatment period, between the placebo and drug condition. LDA is advantageous because it 532
accounts for change over time, includes all data points, and adjusts for the correlation resulting from 533
repeated measures. These LDA models will include variables for treatment, time, and treatment x time
534
interaction. The statistical test for the interaction term will be the measure of a treatment effect. The 535
interaction term will test if the slopes of the regression lines for the liraglutide and placebo groups are 536
different. A group difference (Drug [week 40-week 0] – Placebo [week 40-week 0]) will be reported 537
which corresponds to the interaction term. For the primary outcome of percent change in body weight,
538
only post-baseline data will be used in the LDA model and the difference between treatments at week 40
539
will be reported. These mixed models will allow for random coefficients (intercept and time variable), as
540
well as an appropriate correlation structure for the error terms to account for within-subject
541
correlation. The best model will be chosen using the Akaike Information Criterion-corrected
542
(AICc). The distribution of the outcome measures will be checked for normality, and transformations will
543
be used when necessary. Also, a transformation on the time variable will be considered to optimize the 544
assumed linear relationship.
545
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Additionally, secondary endpoint analyses will be performed on all outcome measures. Using the last
547
observation carried forward (LOCF), baseline to endpoint change scores will be computed for each 548
measure and two-sample t-tests or Wilcoxon rank sum tests will be used to compare these changes 549
between the treatment groups.
550
551
Randomization will be conducted by Genie Groff, the program manager for the Lindner Center of HOPE
552
Research Institute using the program: http://www.randomization.com. Block randomization (with block
553
size of six subjects) will be used to insure relatively equal patients in both the drug and placebo groups.
554
Antipsychotic medications used to treat BP are associated with weight gain and development of obesity
555
(much more so than mood stabilizers). Randomization of subjects will therefore include current
556
antipsychotic use (receiving at least one of the following: asenapine, aripiprazole, cariprazine,
557
chlorpromazine, clozapine, haloperidol, loxapine, olanzapine, paliperidone, perphenazine, quetiapine,
558
resperidone, thiothixene, trifluoperazine, or ziprasidone) as a stratifying factor. Of note, the average
559
number of medications BP patients receive is three. We expect that nearly all patients will be receiving a
560
mood stabilizer and that about 50%-66% of patients will also be receiving an antipsychotic drug.
561
Intermittent missing visits will be treated as missing at random and no special adjustment will be used.
562
The safety population will include all randomized participants with at least one post-baseline safety
563
assessment. Statistical analyses will be conducted by Thomas Blom, MS. All analyses will be conducted
564
using SAS version 9.4 (Cary, N.C., U.S.A.). Hypotheses testing will be two-sided with a significance 565
level of p ≤ 0.05.
566
567
The randomization should balance all demographic and clinical characteristic variables between the two
568
treatment groups and generally no covariates will be used in the analyses. However, if a significant
569
baseline difference exists between treatment groups on a demographic or clinical characteristic variable,
570
this variable will be checked for significant correlations with the outcomes of interest. If a correlation
571
exists, then the variable will be added as a covariate to the efficacy analysis.
572
573
574
DATA HANDLING AND RECORD KEEPING:
575
All data will be compiled using case report forms (CRFs) that will be specifically designed for this
576
study. Trained research coordinators will complete the CRFs. Data from CRFs will be entered and stored
577
in electronic and secured databases at the LCOH.
578
579
ETHICS:
580
The University of Cincinnati (UC) IRB must approve all protocols, informed consent forms, and study 581
procedures prior to opening the study for enrollment. The investigators will comply with all applicable 582
regulatory and legal requirements, ICH GCP guidelines, and the Declaration of Helsinki in obtaining and
583
documenting the informed consent. A completed Informed Consent Document must be obtained from 584
every participant who takes part in a study prior to performing any study-related activities, including
585
screening laboratories, vital signs, or questionnaires. When a potential protocol candidate is identified, the
586
investigator or research coordinator will discuss the study in detail with the potential participant. An
587
explanation of the study, its risks and benefits, and what would be required of the participant is discussed.
588
The participant will be given a copy of the informed consent document to read in a quiet environment
589
without distraction. The participant will be encouraged to take the consent form home so he or she may
590
discuss it with family members. All questions and concerns are addressed throughout this process by the
591
consenter and/or PI.
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593
If a person decides to participate, he/she is asked to sign the informed consent document only after all
594
questions and concerns have been addressed and the consenter is satisfied that there is a clear
595
understanding of the trial.
596
597
The informed consent document must be signed and dated by the participant or legal representative along
598
with the coordinator or investigator obtaining consent.
599
600
The original signed informed consent will be kept in the participant’s research chart (i.e., source
601
documents) or in the participant’s medical record as required by the research unit.
602
603
The participant will be given a copy of the signed informed consent document that has HIPPA language
604
written into the consent.
605
606
The study will be conducted in accordance with the Declaration of Helsinki.
607
608
The study will be conducted in accordance with the ICH GCP guidelines.
609
610
STUDY SCHEDULE:
611
We anticipate recruiting approximately 4 participants per month. We therefore anticipate that total
612
enrollment will take up to 15 months, and total study duration will be up to 24 months. We expect the first
613
participant to be enrolled in September 2016. Following discontinuation of the last study participant, we
614
will clean and analyze the data and write the manuscript for publication, which will take approximately 3
615
months.
616
617
STUDY DRUGS AND MATERIALS:
618
Study medication will be dispensed through prefilled dial-a-dose pens containing 18 mg of liraglutide or
619
placebo, and the participant can select doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg and 3 mg. The pen is
620
made to be used with NovoFine® or NovoTwist® disposable needles up to a length of 8 mm.
621
622
Packaging and Labelling of Study Medication(s)
623
Participants will be dispensed a prefilled dial-a-dose pen containing 18 mg of liraglutide or placebo that
624
will be labeled according to Ohio regulations and Annex 13 with the name of the Principal Investigator; 625
drug or placebo; date dispensed; and participant number and initials. The pen will be used until
626
medication is finished depending on the participant’s dosing schedule and a new one will be dispensed.
627
628
Storage and Drug Accountability of Study Medication(s)
629
New, unused liraglutide pens will be kept in the LCOH research lab refrigerator at 36°F to 46°F (2°C to 630
8°C). Pens will not be frozen. Participants will be instructed to keep their pens in use for 30 days at 59ºF
631
to 86ºF (15ºC to 30ºC) or in a refrigerator at 36°F to 46°F (2°C to 8°C). They will also be instructed to not
632
freeze the pens and to protect the pens from light.
633
634
The temperature in the laboratory refrigerators is controlled automatically and temperatures are recorded
635
daily. The investigator will ensure the availability of proper storage conditions and record and evaluate
636
the temperature.
637
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No trial medication will be dispensed to any person not enrolled in the study. All unused medication(s) 639
will be stored separately from used trial medication(s). Drug accountability for all trial product(s) on the
640
participant and trial site level will be performed by trained research coordinators and pharmacy staff. For
641
participants, accountability will be performed at every visit; on site level the accountability will be
642
performed every 3 months. Return of used/unused trial product(s) and destruction of returned trial product
643
will be performed following Sponsor and Site SOPs.
644
645
Auxiliary Supply
646
No special equipment or other ancillary supplies are expected to be needed for this trial.
647
648
Randomization and Blinding
649
This is double-blind, placebo controlled trial. Pens containing active study medication and those
650
containing placebo will be identical in appearance. The randomization list will be generated by Ms. Genie
651
Groff, the program manager for the Lindner Center of HOPE Research Institute, using
652
http://www.randomization.com. Block randomization method will be used (in blocks of six subjects) to 653
ensure a balanced number of subjects get active drug and placebo, and to prevent long sequences of one
654
treatment assignment. Treatment allocation will be known by one unblinded member of the research staff
655
(Ms. Genie Groff, who generated the randomization list) and kept at a secure location (a locked cabinet in
656
the LCOH Research Institute).
657
Breaking of Blinded Codes
658
The code for a particular participant may be broken in a medical emergency if knowing the identity of the
659
treatment allocation would influence the treatment of the participant or if demanded by the participant. 660
661
Whenever a code is broken, the person breaking the code (Ms. Genie Groff) will record the time, date and
662
reason as well as his/her initials in the source documents. If a blind must be broken on an emergent basis,
663
Ms Groff will be contacted. Her work number is 513-536-0715. Of note, Ms. Groff is available
664
24hours/day, 7 days a week by cell phone (513-276-8388).
665
666
The Sponsor will be notified immediately if the code needs to be broken.
667
668
All codes (whether broken or not) must be kept throughout the trial period. Accountability of all broken
669
or unbroken codes (hard copy and electronic) will be performed at or after trial closure.
670
671
CONCOMITANT ILLNESSES AND MEDICATIONS:
672
673
Definitions:
674
Concomitant illness: any illness that is present at the start of the trial (i.e. at the first visit).
675
Concomitant medication: any medication other than the trial product(s) that is taken during the trial,
676
including the screening and run-in periods.
677
678
Details of all concomitant illnesses and medication will be recorded at trial entry (i.e. at the first visit).
679
Any changes in concomitant medication will be recorded at each visit. The information collected for each
680
concomitant medication will include start date, stop date or continuing, dosage, and indication.
681
682
For each concomitant illness, date of onset, date of resolution or continuing, and relationship to
683
investigational medication will be recorded.
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684
685
686
RISKS AND DISCOMFORTS ASSOCIATED WITH LIRAGLUTIDE (Saxenda®):
687
Liraglutide 3.0 mg sc injection is contraindicated in patients with a personal or family history of
688
medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia Syndrome type 2.
689
Liraglutide 3.0 mg sc injection is also contraindicated in patients with a prior serious hypersensitivity
690
reaction to Victoza or to any of the product’s components and in women who are pregnant. Common non-
691
serious side effects of liraglutide 3.0 mg sc injection include nausea, diarrhea, constipation, vomiting,
692
headache, decreased appetite, upset stomach, tiredness, dizziness, stomach pain, and changes in lipase
693
levels in the blood.
694
695
Possible serious adverse reactions of liraglutide 3.0 mg sc injection include:
696                             Risk of Thyroid C-Cell Tumors
697
Acute Pancreatitis
698
Acute Gallbladder Disease
699
Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy
700
Heart Rate Increase
701
Renal Impairment
702
Hypersensitivity Reactions
703
Suicidal Behavior and Ideation
704
705
Liraglutide 3.0 mg sc injection is Pregnancy Category X. Therefore, pregnant or lactating women, or
706
women not using adequate birth control, will not be allowed in the study.
707
708
Investigators will be available 24 hours/7 days/week for emergencies for study participants. Additional
709
visits to monitor emerging symptoms will be scheduled as needed. The use of all medications will be
710
recorded throughout the study.
711
712
Adverse Event Reporting and Definitions:
713
714
Definitions
715
716
Adverse Event (AE):
717
An AE is any undesirable medical event occurring to a participant in a clinical trial, whether or not related
718
to the trial product(s). This includes events reported from the first trial related activity after the participant
719
has signed the informed consent and until post treatment follow-up period as defined in the protocol. The
720
following should not be recorded as AEs, but recorded as medical history/concomitant illness on the CRF
721
at screening:
722
     Pre-planned procedure, unless the condition for which the procedure was planned has worsened
723                      from the first trial related activity after the participant has signed the informed consent
724
     Pre-existing conditions found as a result of screening procedures
725
726
Clinical Laboratory Adverse Event:
727
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically significant – i.e. an
728
abnormality that suggests a disease and/or organ toxicity and is of a degree of severity that requires active
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729
management, (i.e. change of dose, discontinuation of trial product, more frequent follow-up or diagnostic
730
investigation).
731
732
Serious Adverse Event (SAE):
733
A serious AE is an experience at any dose that results in any of the following:
734                    Death
735
     A life-threatening* experience
736
     In-patient hospitalisation or prolongation of existing hospitalization
737
     A persistent or significant disability/incapacity
738
     A congenital anomaly/birth defect
739
     Important medical events that may not result in death, be life-threatening*, or require
740
hospitalization may be considered an SAE when, based upon appropriate medical judgement, they
741
may jeopardise the participant and may require medical or surgical intervention to prevent one of
742
the outcomes listed in this definition
743
     Suspicion of transmission of infectious agents
744
745
*The term life-threatening in the definition of SAE refers to an event in which the participant was at risk
746
of death at the time of the event. It does not refer to an event which hypothetically might have caused 747
death if it was more severe.
748
749
The following adverse events must always be reported as an SAE using the important medical event 750
criterion if no other seriousness criteria are applicable: 1) suspicion of transmission of infectious agents
751
via the trial product; and 2) risk of liver injury defined as alanine aminotransferase (ALT) or aspartate
752
aminotransferase (AST) >3 times the upper limit of normal.
753
754
Serious Adverse Drug Reaction (SADR):
755
An adverse drug reaction (ADR) is an adverse event for which a causal relationship (Possible/Probable
756
relation) between the study drug and the occurrence of the event is suspected. The ADR should be
757
classified as serious if it meets one or more of the seriousness criteria.
758
Medication Errors:
759
A medication error concerning trial products is defined as: administration of wrong drug or use of wrong
760
device; wrong route of administration, such as intramuscular instead of subcutaneous; administration of
761
an overdose with the intention to cause harm, misuse, or abuse of trial product; or accidental
762
administration of a lower or higher dose than intended. However, the administered dose must deviate
763
from the intended dose to an extent where clinical consequences for the trial subject were likely to happen
764
as judged by the investigator, although they did not necessarily occur.
765
766
Non-Serious Adverse Event:
767
A non-serious AE is any AE which does not fulfil the definition of an SAE.
768
769
Severity Assessment Definitions:
770
     Mild: Transient symptoms, no interference with the participant’s daily activities
771
     Moderate: Marked symptoms, moderate interference with the participant’s daily activities
772
     Severe: Considerable interference with the participant’s daily activities, unacceptable
773
774
Relationship to study medication Assessment Definitions:
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775
     Probable: Good reasons and sufficient documentation to assume a causal relationship
776
     Possible: A causal relationship is conceivable and cannot be dismissed
777
     Unlikely: The event is most likely related to an etiology other than the trial product
778
779
Outcome Categories and Definitions:
780
     Recovered: Fully recovered or by medical or surgical treatment the condition has returned to the
781                      level observed at the first trial related activity after the participant signed the informed consent 782
     Recovering: The condition is improving and the participant is expected to recover from the event.
783                      This term should only be used when the participant has completed the trial
784
     Recovered with sequelae: As a result of the AE, the participant suffered persistent and significant
785                      disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered with sequelae should
786                      be rated as an SAE.
787
     Not recovered
788
     Fatal: This term is only applicable if the subject died from a condition related to the reported AE.
789                      Outcomes of other reported AEs in a subject before he/she died should be assessed as
790
“recovered/resolved”, “recovering/resolving”, “recovered/resolved with sequelae” or “not
791
recovered/not resolved.” An AE with fatal outcome must be reported as an SAE.
792
     Unknown
793
794
795
796
The sites will collect the following information at minimum for each SAE and provide it to the University
797
of Cincinnati IRB and Novo Nordisk within 72 hours:
798
1. Study name
799
2. Patient identification (e.g. initials, sex, age)
800
3. Event (preferably a diagnosis)
801
4. Drug
802
5. Reporter identification (e.g. Name, or initials)
803
6) Causality
804
7) Outcome
805
806
Collection, Recording and Reporting of Adverse Events
807
All events meeting the definition of an adverse event must be collected and reported from the first trial
808
related activity after the participant has signed the informed consent and until the end of the post-
809
treatment follow-up period as stated in the protocol. The site intends to comply with all local legal,
810
regulatory, and IRB requirements related to AE reporting. The site and the principal investigator will be
811
responsible for reporting of adverse events including SAEs, suspected unexpected serious adverse
812
reactions (SUSARs), and SADRs, to the competent authority and University of Cincinnati Institutional
813
Review Board based upon federal regulations and local IRB policies. All SAEs will be reported to the
814
IRB and Novo Nordisk within 72 hours. In addition, the site and principal investigator will report to Novo
815
Nordisk all SADRs or any other event reported to regulatory authorities. The events shall be sent to Novo
816
Nordisk at time of submission to health authorities or within 15 days from the site becoming aware of
817
such adverse events, whichever comes first.” Follow-up of Adverse Events
818
During and following a participant’s participation in a clinical trial, the investigator will carefully assess
819
and provide adequate medical care to the study participant for any study-related adverse events, including
820
clinically significant laboratory values related to the study. The Lindner Center of HOPE will decide on a
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19

821
case by case basis whether to reimburse the participant for their out of pocket health care expenses. This
822
will be determined by the medical director of LCOH who is not a part of the study team. Medical
823
expenses that are deemed clearly related to study participation will be reimbursed. (This language will be
824
included in the consent form.)
825
826
All adverse events classified as serious or severe or possibly/probably related to the trial product will be
827
followed until the participant has recovered and all queries have been resolved. For cases of chronic
828
conditions, follow-up until the outcome category is “recovered” is not required, as these cases can be
829
closed with an outcome of “recovering” or “not recovered.”
830
831
All other adverse events will be followed until the outcome of the event is “recovering” (for chronic
832
conditions), or “recovered” or until the end of the post-treatment follow-up stated in the protocol, 833
whichever comes first, and until all queries related to these AEs have been resolved.
834
835
Pregnancy
836
All female study participants will be instructed to notify the site and the investigator immediately if they
837
become pregnant. The investigator must follow the pregnancy until the pregnancy outcome and the
838
newborn infant is one month of age. The investigator must report to Novo Nordisk about the pregnancy,
839
pregnancy outcome, and health of the newborn infant(s), as well as AEs in connection with the
840
pregnancy, and AEs in the foetus and newborn infant. Reporting of pregnancy by the investigator will
841
occur within the same timelines described above for reporting of Adverse Events. Pregnancy
842
complications will be recorded as adverse event(s). If the infant has a congenital anomaly/birth defect this
843
will be reported and followed up as a serious adverse event.
844
845
Precautions/Over-dosage
846
Effects of overdose when treated with liraglutide might include severe nausea and severe vomiting. In the
847
event of overdosage, appropriate supportive treatment will be initiated according to the participant’s
848
clinical signs and symptoms. All participants in the trail will be appropriately educated on how to use the
849
pen in order to avoid overdosing and how to proceed in event of accidental overdosing
850
851
LIABILITY AND PARTICIPANT INSURANCE:
852
853
In the event that a participant becomes ill or injured from participating in this research study, emergency
854
medical care will be provided to them. The Lindner Center of HOPE and University of Cincinnati College
855
of Medicine will decide on a case by case basis whether to reimburse the participant for their out of
856
pocket health care expenses.
857
858
The principal investigator will be responsible for the conduct of the study and Lindner Center of HOPE
859
agrees to defend, indemnify, and hold harmless Novo Nordisk, any of its parent companies, affiliates, or
860
subsidiaries, and their respective officers, directors, employees, agents, representatives, distributors,
861
salespersons, customers, licensees, and end-users from and against any claim, suit, demand, loss, damage,
862
expense or liability imposed by any third party arising from or related to: (a) any breach of sponsor-
863
investigator's obligations or representations; or (b) investigator’s negligent or grossly negligent use or
864
willful misuse of the study drug, the results, or services derived therefrom. This indemnification shall not
865
apply in the event and to the extent that a court of competent jurisdiction or a duly appointed arbiter
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866
determines that such losses or liability arose as a result of Novo Nordisk’s gross negligence, intentional
867
misconduct, or material breach of its responsibilities.
868
869
PUBLICATION PLAN:
870
We will submit abstracts of the study results to psychiatric and obesity scientific meetings such as the
871
American Psychiatric Association Annual Meeting, Obesity Week, and the Society of Biological
872
Psychiatry. We will also submit a manuscript of the study for publication to a leading obesity or 873
psychiatric journal, such as Obesity, the American Journal of Psychiatry, or the Journal of Clinical
874
Psychiatry. We will register the study with a publicly assessable database such as clinicaltrials.gov.
875
876
Fasting Blood Script for Phone Screens:
877
878
During the screening visit we will obtain a fasting blood sample. Fasting blood tests require you to stop 879
eating and drinking anything (with the exception of plain water) at least 8 hours before you visit. Please 880
drink as much water as you like, but no other food or drink. Black coffee or black tea - without any
881
sweetener or creamer - is acceptable. After the blood draw we will provide a snack and drink. If you have 882
a medical condition that prevents you from fasting 8 hours, please let us know before the visit and we will 883
make other arrangements. Please let us know if you have any questions about the fasting procedures.
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21

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2.
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Ebdrup BH, Knop FK, Ishoy PL, Rostrup E, Fagerlund B, Lublin H, et al. Glucagon-like peptide-1
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39.
Lykkegaard K, Larsen PJ, Vrang N, Bock C, Bock T, Knudsen LB. The once-daily human GLP-1
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Sharma AN, Ligade SS, Sharma JN, Shukla P, Elased KM, Lucot JB. GLP-1 receptor agonist
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Dixit TS, Sharma AN, Lucot JB, Elased KM. Antipsychotic-like effect of GLP-1 agonist liraglutide
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Alexander J, Cheng YH, Choudhary J, Dinesh A. Phentermine (Duromine) precipitated psychosis.
Aust N Z J Psychiatry. 2011;45(8):684-5.
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bupropion. Addict Sci Clin Pract. 2013;8:22.
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Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, et al. The International
Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders.
Am J Psychiatry. 2013;170(11):1249-62.
53.
Grant P, Lipscomb D, Quin J. Psychological and quality of life changes in patients using GLP-1
analogues. J Diabetes Complications. 2011;25(4):244-6.
54.
Stunkard AJ, Messick S. The three-factor eating questionnaire to measure dietary restraint,
disinhibition and hunger. J Psychosom Res. 1985;29(1):71-83.
55.
Gormally J, Black S, Daston S, Rardin D. The assessment of binge eating severity among obese
persons. Addict Behav. 1982;7(1):47-55.
56.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and
sensitivity. Br J Psychiatry. 1978;133:429-35.
57.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J
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Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global
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59.
Posner K, Brent D, Lucas C, al. E. Columbia-Suicide Severity Rating Scale (C-SSRS). New York,
NY: New York State Psychiatric Institute; 2009.
60.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Revised. Arlington, VA: American Psychiatric Association; 2013.
61.
First M, Williams J, Spitzer R, Gibbon M. Structured Clinical Interview for DSM-IV-TR Axis I
Disorders, Clinical Trials Version (SCID-CT). New York: Biometrics Research, New York State
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Table 1: Schedule of Assessments
Visit
Assessment Week
Assessment Day
Informed consent
Psychiatric evaluation
Medical history
SCID
Mental Status
Examination
Inclusion/exclusion
criteria
Physical examination
Demographics
Vital signs
Heighta
Weighta
Waist circumference
Clinical laboratory
testsb
12-lead ECG
Serum pregnancy test
Urine Pregnancy test
Urine drug screen
YMRS
MADRS
CGI-BP-S
-1
(Screening)
up to -4
-3 to -28
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
0
(Baseline)
0
0
x
x
x
x
x
x
x
x
x
1
2
3
4
5
6
7
8
1
2
3
4
6
8
10
12
7
14
21
28
42
56
70
84
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
9
10
11
12
13
14
15
14
16
20
24
28
32
36
98
112
140
168
196
224
252
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
16/ET
17
(Follow-up)
40
41
280/ET
287/Any
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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1
CGI-BP-I
Lifestyle counseling
TFEQ
BES
C-SSRS- Baseline
x
Version
C-SSRS- Since Last
Visit Version
Suitability to remain in
x
study
Investigational
product dispensed
Investigational
product returned
Compliance assessed
Concomitant
x
medications
Adverse events
x
Drug interaction form
x
Termination record
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
aWeight (using a calibrated scale) and height to be measured without shoes.
bLaboratory samples will be obtained when the subject is fasting and will include CBC with diff, Metabolic profile, lipids, HgA c. Participants must
fast for 12 hours prior to laboratory samples being collected.
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Figure 1: Study Schematic
N= 90
N= 60
Ns:
N= 30
Liraglutide
Saxenda®
N= 30
Placebo
Screening
Phase:
3-28 days
Randomization
Double Blind Treatment Phase
40 weeks
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Potential Drug Interaction
Subject #: ______________
Date:_______________
1. Was there any information suggesting the subject had an interaction between liraglutide and a
psychiatric mediation?
☐Yes
☐No
If YES, provide a complete description of the putative interaction.
2. Please list all psychiatric medications involved in this interaction.
3. Was any action taken to manage the interaction?
☐Yes
☐No
If YES, please explain:
4. Outcome of interaction:
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