Pilot Phase 1/2, Open-Label, Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Phase: PHASE1
Conditions: Myalgic Encephalomyelitis, Chronic Fatigue Syndrome
Sponsor: LUCINDA BATEMAN, MD

CONFIDENTIAL 
Physician-Sponsored Investigational New Drug Application
1.
CLINICAL TRIAL PROTOCOL
PILOT PHASE 1/2, OPEN-LABEL, CLINICAL TRIAL TO 
InVESTIGATE CT38 iN THE TREATMENT OF MYALGIC 
ENCEPHALOMYELITIS / CHRONIC FATIGUE 
SYNDROME (InTiME)
Protocol Title:
InTiME
Protocol Number:
ME-101p
Protocol Date:
May 25, 2018, Amended July 3, 2018 (version 1.2); Amended October 26, 2018 
(version 1.51), Amended December 7, 2018 (version 1.62)
Development Phase:
1/2
Drug Substance:
CT38
Principal Investigator:
Lucinda Bateman, MD
IND Sponsor
Lucinda Bateman, MD 
Founder & Medical Director 
Bateman Horne Center 
24 South 1100 East 
Suite 205 
Salt Lake City, UT  84102
Medical Monitor
Hunter Gillies, MD
Version Number
1.62
clinicaltrials.gov
NCT03613129
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PROTOCOL APPROVAL SIGNATURE PAGE 
Protocol Title:
InTiME
Protocol Number:
ME-101p
Reviewed and Approved by: 
________________________________________________________ 
Lucinda Bateman, MD, Principal Investigator
________________________________________________________ 
Hunter Gillies, MD, Medical Monitor 
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LISTING OF ABBREVIATIONS AND DEFINITION OF TERMS
5HT:  Serotonin
5HT1A:  Serotonin receptor subtype
AE:  Adverse event
AUC:  Area under the plasma concentration-
time curve from time zero to inﬁnity
BNST:  Bed nucleus of the stria terminalis
BP:  Blood pressure
BPM:  Beats per minute
CFS:  Chronic Fatigue Syndrome
Cmax:  Maximum plasma concentration
CPET:  Cardio-pulmonary exercise test
CRF:  Corticotropin-releasing factor
CRF1, CRF2:  Corticotropin-releasing factor 
receptor, subtype(s) 1 and 2 
Css:  Plasma concentration at steady state
CT37:  Originally PG-873637
CT38:  Originally PG-873638 (free base)
CT38s:  Originally PG-968041, acetate salt of 
CT38
EEG:  Electroencephalography
eGFR:  Estimated glomerular ﬁltration rate
FDA:  Food and Drug Administration
HPA:  Hypothalamic-pituitary-adrenal
HR:  Heart rate
IB:  Investigator’s Brochure
ICH:  International Conference on 
Harmonization
IND:  Investigational New Drug
IRAE:  Immediately reportable adverse event
IRB:  Institutional Review Board
ME:  Myalgic Encephalomyelitis
MTDb:  Maximum tolerated dose by bolus
OI:  Orthostatic intolerance
PEM:  Post-exertional malaise
PI:  Principal Investigator
PD:  Pharmacodynamic
PK:  Pharmacokinetic
RAND36:  Medical Outcomes Survey (similar 
to Short Form-36)
RER:  Respiratory exchange ratio
RPE:  Rating of perceived exertion
SAE:  Serious adverse event
SC:  Subcutaneous
SNRI:  5HT and norepinephrine re-uptake 
inhibitor
SSRI:  Selective 5HT re-uptake inhibitor 
t1/2,z:  Terminal elimination half-life
VAS:  Visual analogue scales
VCO2:  Carbon dioxide production
Ve:  Minute ventilation
VO2:  Oxygen consumption
VT:  Ventilatory threshold
UCN2, UCN3:  Urocortins 2 and 3 
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PROTOCOL SYNOPSIS
Title
InTiME:  Pilot Phase 1/2, Open-Label, Clinical Trial to Investigate CT38 in the 
Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
Indication
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Protocol 
Number
ME-101p
Study Sponsor
Lucinda Bateman, MD 
Bateman Horne Center
Principal 
Investigator
Lucinda Bateman, MD 
Bateman Horne Center
Study Sites
The study will be conducted at a single center in the US.
Clinical Phase
1/2
Study Period
Planned duration of the study (for each patient):  9 weeks
Planned recruitment period:  12 weeks
Objectives
To evaluate the efﬁcacy of CT38 in the treatment of ME/CFS, based on changes in 
patient-reported symptoms (e.g., fatigue, pain, sleep, cognition, orthostatic 
intolerance, temperature, ﬂu-like, headaches or sensitivities, shortness of breath, 
gastrointestinal, urination, anxiety, depression), hours of upright activity, functional 
capacity (activity, sleep quality, energy expenditure, heart rate), and general health 
status (global change, vitals)
To evaluate the effect of CT38 on orthostatic intolerance
To gain preliminary insights on the safety and tolerability of CT38 in ME/CFS 
patients
Study Design
Single-center, open-label, 3-arm Phase 1/2 clinical trial
The study is comprised of a screening and recruitment period, a 4-week pre-
treatment assessment period, a 1-week interventional treatment period, and a 4-
week post-treatment assessment period
Duration of 
Treatment
3.5 hours at each of Visits 3, 4 and 4b (total of 10.5 hours)
Number of 
Patients
Total of 18, with at least 3 in each of D1 and D2 dose groups (sequentially-dosed) 
and the remainder allocated to a ﬁnal dose determined by D1/D2 tolerability
Study Agent
CT38s, a peptide agonist selective for the corticotropin-releasing factor receptor 
subtype 2, delivered by subcutaneous administration
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Dosing
The study will utilize a continuous subcutaneous infusion at 3 dose levels.  The 
planned Low-dose delivered ~0.8 μg/kg over 3.5 hours (on 2 separate treatment 
days), was associated with clinically signiﬁcant hemodynamic changes, and is 
closed out.
The revised doses will deliver 0.11 and 0.35 μg/kg by continuous subcutaneous 
infusion.
Inclusion 
Criteria
Able to read, understand and voluntarily sign the informed consent form
18-60YO male or female, meeting Fukuda, Canadian and IOM criteria for ME/CFS, 
and relatively stable state of illness for the past 3 months
Agree to refrain from taking medications that would affect assessment of the 
effectiveness of study medication for the duration of the study
Living at an altitude between 3,500 and 5,500 feet above sea level for the past 1 year
Availability for the duration of the study
Have mobile (smart) phone and access to the internet
Exclusion 
Criteria
Alternate medical or psychiatric illness that explains ME/CFS symptoms
Active or uncontrolled co-morbidities (including depression, untreated endocrine 
diagnoses, recent acute infection, the presence of a supra-ventricular tachycardia or 
ventricular tachycardia, severe baseline hypotension, etc), which in the opinion of 
the PI may interfere with the ability of the patient to participate in the study
Pregnancy, or while breast feeding
Cigarette smoker or former smoker who has smoked within 6 months of the study
Renal impairment, Body Mass Index > 35, or evidence of substance abuse
Participating in another clinical treatment trial, or symptoms improving as a result 
of treatment intervention in the past 3 months
Current treatment with medications that interact with the 5HT, norepinephrine, 
dopamine or cortisol pathways
Treatment with short-term antivirals/antibiotics within 4 weeks, Rituximab™ 
within 6 months, or anti-retrovirals within 1 year, of entry into the trial.
Efﬁcacy 
Evaluation
Primary Endpoint:  The change in patient-reported daily symptom levels
Secondary Endpoints, include a determination of treatment-related effects on 
functional capacity, orthostatic intolerance and general health status
Safety 
Evaluation
Adverse events occurring after patient enrollment through to the ﬁnal visit to the 
clinic, will be assessed and recorded.  Serious adverse events deemed related to 
study treatment will be followed until resolution or stabilization of the event.
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SCHEMATIC OF STUDY DESIGN 
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1
15
29
8
22
36
43
50
57
64
Pre-℞ Assessment
4 weeks
Post-℞ Assessment
4 weeks
℞
1 week
Visit 6
Day 64 
• SF36
• Vitals
• OI test
Visit 3
Day 29 
• SF-36
• Vitals
• Urine
• ℞
• Blood 
(PK)
Visit 4
Day 31 
• Vitals
• ℞
• Blood 
(PK)
Visit 1
Day 1 
• Consent
• SF-36
• Vitals
• Urine
• Blood 
(eGFR)
• OI test
Continuous FitBit™ (activity, sleep, HR), 
daily VAS, and hours of upright activity
Visit 4b
Day 33 
• Vitals
• ℞
• Blood 
(PK)
Recruitment

CONFIDENTIAL 
Physician-Sponsored Investigational New Drug Application
1.1.
Introduction
1.1.1.
Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), also known as systemic exertion 
intolerance disease, is a complex disorder that may be triggered by infection or other stressors (e.g., 
emotional or physical trauma, immune activation, chemical exposures).  Its hallmark is a reduced 
capacity for physical and mental activity manifest as profound fatigue along with a cascade of 
debilitating symptoms (including pain, cognitive dysfunction, orthostatic intolerance, sensitivities, and 
irregularities of the autonomic, immune and metabolic systems) that worsen with activity (referred to as 
post-exertional malaise or PEM), are not improved by sleep, and can persist for years.  ME/CFS affects up 
to 2.5 million Americans and results in annual direct and indirect economic costs between $17 and 24 
billion in the US.  There are no approved therapeutics for ME/CFS.  Patients are often unable to handle 
the activities of daily living and experience a loss of career and a very poor quality of life [IOM 2015].
The etiology of ME/CFS is unknown.  The disease is often thought of as a stress- and/or neuroendocrine-
related complication, with patients showing abnormalities of the hypothalamic-pituitary-adrenal (HPA) 
axis and of the immune, metabolic, norepinephrine and serotonin (5HT) systems.  In young animals, 
intense stress can bring about an up-regulation and relocation of the corticotropin-releasing factor 
receptor subtype 2 (CRF2) to the membranes of 5HT neurons in the raphe nuclei (i.e., the source of 5HT in 
the brain and cord) and limbic system, which can persist into adulthood.  In this conﬁguration, a minor 
stress stimulates (rather than inhibits) the release of 5HT from the raphe nuclei and throughout the limbic 
system, and the excess of 5HT leads to a desensitization of the 5HT1A autoreceptor and compromised 5HT 
regulation [Wood 2013, Neufeld-Cohen 2012, Lukkes 2009a, Lukkes 2009b, Waselus 2009, Lukkes 2008].  Cortene Inc. (see below) has 
postulated that ME/CFS results from such CRF2 up-regulation and relocation, and relative to healthy 
subjects, ME/CFS patients show increased brain and/or hypothalamic 5HT [Dinan 1997, Sharpe 1997, Bearn 1995, 
Cleare 1995, Bakheit 1992], 5HT1A desensitization [Cleare 2005] and higher positivity for 5HT serum antibodies that 
correlate with increased physio-somatic symptom scores (muscle pain, autonomic symptoms, ﬂu-like 
malaise) and sadness [Maes 2013].  This hypothesis of a CRF2 maladaptation, resulting in an excess of 5HT 
under subsequent stress, comprehensively explains the symptoms and anomalies of ME/CFS.  However, 
in the absence of an animal model of ME/CFS, the hypothesis can only be investigated in humans.
1.1.2.
Investigational Agent
CT38 [proprietary data redacted] is a custom [proprietary data redacted] CRF2-selective, peptide 
agonist…[proprietary data redacted] comprised of naturally-occurring amino acids, and is easily 
synthesized [Investigator’s Brochure or IB].
CT38 was previously ﬁled under investigational new drug (IND) application [proprietary data redacted], 
with the Division of Metabolism and Endocrine Drug Products at the Food and Drug Administration 
(FDA), to evaluate its effect in preventing muscle atrophy and wasting associated with various disease 
conditions.  Completed studies included all the pre-IND studies (necessary for an acute indication) as 
well as a Phase 1 clinical trial in healthy humans.  Full study reports were submitted to the FDA under 
IND [proprietary data redacted], and there were no outstanding issues when the IND was voluntarily 
withdrawn in 2008 (for strategic reasons unrelated to CT38).  Cortene Inc. (“Cortene”) licensed CT38 
along with the right of reference to IND [proprietary data redacted].
1.1.2.1.
In Vitro Pharmacology
CT38, CT38s (acetate salt of CT38, [proprietary data redacted]), CT37 (backup lead, [proprietary data 
redacted]), UCN2 and urocortin 3 (UCN3, endogenous CRF2-selective peptide) were evaluated for 
selectivity and potency against CRF1 (via A7r5 rat aortic cell lines) and CRF2 (via Y-79 human 
retinoblastoma cell lines), by measuring cyclic adenosine monophosphate (cAMP) formation after 
treatment with the compound of interest.  CT38 was found to have a greater than 50-fold selectivity for 
CRF2 over CRF1, and comparable CRF2 potency to UCN2 [IB].
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1.1.2.2.
In Vivo Pharmacology
In vivo, CT38, CT37 and other custom CRF2 agonists show similar beneﬁcial effects to UCN2 and/or 
UCN3, in animal models of muscle wasting (due to casting, denervation, corticosteroid excess, 
dystrophin-deﬁciency), tumor growth and metastases, inﬂammation, obesity, GI transit time and the 
cardiovascular system, speciﬁcally changes in heart rate (HR) and blood pressure (BP) [IB].
1.1.2.3.
Safety Pharmacology and Toxicology
There is little or no binding of CT38 when tested against various receptors, transporters, ion channels and 
enzymes, other than CRF1 (weakly binding at very high concentrations).  CT38 does not cause QT 
prolongation in vitro (in human ether-a-go-go related gene or hERG channel and Purkinje ﬁber assays) 
and in vivo (rats and monkeys).  In vivo safety pharmacology studies demonstrate that high doses of CT38, 
administered as CT38s by the subcutaneous (SC) route, has pharmacological effects on the central 
nervous system (drop in spontaneous motor activity, decreased body temperature, tremors and subdued 
behavior), respiratory system (decreased respiratory rate and tidal volume), cardiovascular system 
(tachycardia, hypotension), gastrointestinal system (decreased transit time), and renal system (enuresis 
and diuresis) [IB].
Toxicology studies (mouse, rat, dog, rabbit, monkey, human in vitro) show that CT38 (administered as 
CT38s by the SC route) has large safety margins with mostly mild, dose-dependent, transient and 
reversible effects.  CT38 is not genotoxic (in vitro Ames and chromosome aberration assays), has no effect 
on corticosterone and aldosterone levels, and in 1-month repeat dose toxicology studies in rats and 
monkeys, there was little or no drug accumulation and no antibody formation (histology).  CT38 is 
eliminated by renal ﬁltration and the terminal elimination half-life (t1/2,z) is < 2 hours [IB].
In animals, CT38 administered by SC injection (bolus) causes transient, but dose-related increases in HR 
and decreases in BP, similar to UCN2 and UCN3.  These were shown to be much reduced under SC 
infusion, potentially explained by a lower maximum plasma concentration (Cmax).  However, under 
continuous SC infusion in rats, the complete absence of tachycardia or hypotension even at dose levels 
10,000 times higher than the bolus doses that cause such HR and BP changes, suggests that continuous SC 
infusion induces receptor (CRF2) endocytosis.  This is consistent with studies showing that the 
endocytosis of CRF2 is a function of agonist potency, concentration and duration of exposure [IB].
1.1.2.4.
Phase 1 Clinical Trial
CT38s was administered by SC injection (bolus) in a sequential, single ascending dose, randomized, 
double-blind, placebo-controlled trial in healthy male subjects.  There were no deaths or serious adverse 
events (SAEs).  Adverse events (AEs) were generally mild and anticipated from CRF2 pharmacology.  
Escalating dose (in μg/kg) ﬁrst caused HR increases at 0.200; tachycardia (> 100 beats per minute or BPM 
at rest) at 0.833; and hypotension at 1.67.  The only AE classiﬁed as severe was a single subject with 
tachycardia (160 BPM) at a dose of 1.667 μg/kg (resolved with propranolol).  The maximum tolerated 
dose by bolus (MTDb) was deemed to be 0.833 μg/kg, which showed mild tachycardia without 
hypotension.  The t1/2,z was 1-3 hours.  CT38 was not detectable in the plasma 8 hours post-dose.  All 
laboratory results (including cortisol levels and QTc changes) were comparable to placebo, except for 
white blood cell counts, which were slightly elevated in the highest dose groups, but had resolved by the 
following day.  The clinical study report was submitted to FDA and there were no outstanding concerns 
when the IND was voluntarily withdrawn [IB].
1.1.2.5.
CT38 in ME/CFS
If ME/CFS results from an up-regulation/relocation of CRF2 and a maladapted stress response as 
postulated above, then prolonged receptor stimulation via a CRF2 agonist such as CT38, could potentially 
induce CRF2 endocytosis (as demonstrated by SC infusion in rats), which could be curative.  In addition, 
CT38 and other CRF2 agonists can modulate many of the individual abnormalities of the disease (e.g., the 
HPA axis, the immune system, cortisol, glucose).
There is no animal model of ME/CFS.  Moreover, speciﬁc changes in CRF2 expression on speciﬁc neurons 
of the raphe nuclei and limbic system, along with any resulting excess of 5HT in these neurons under 
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stress, cannot be measured in a live system—though such changes have been demonstrated in animal 
biopsies.  Therefore, assuming the hypothesized etiology is correct, the only possible way to investigate 
effect in humans is via a clinical trial.  Given that CT38 has shown virtually identical pharmacology to the 
endogenous CRF2 agonists UCN2 and UCN3, both in vitro and in vivo, and has been shown to be safe and 
tolerable in a Phase 1 trial in healthy human subjects, the Principal Investigator (PI), Lucinda Bateman, 
MD, a clinician with expertise in the diagnosis, treatment and study of ME/CFS, plans to evaluate CT38 
as a candidate therapeutic for the treatment of ME/CFS.
1.1.2.6.
Initial Experience in ME/CFS Patients
The ﬁrst 2 patients dosed under this protocol exhibited hemodynamic changes as the infusion progressed 
(i.e., dose-related).  These changes included increased HR (baselines of 47 and 92 BPM, increasing to 
respective maximums of 89 and 111 BPM, towards the end of the infusion) and decreased BP (baselines of 
105/68 and 108/74 mmHg, decreasing to respective minimums of 110/56 and 100/50 mmHg).  The 
associated pharmacokinetic (PK) data… [proprietary data redacted].  This increased sensitivity of the 
CRF2 pathway supports the notion that CRF2 may be up-regulated in ME/CFS patients relative to healthy 
subjects.
Referring to the IB (section 4.1.1.4.), a concentration of between… [proprietary data redacted].  The 
hemodynamic effects induced in the ﬁrst 2 patients dosed under this protocol suggests that the initial 
dose… [proprietary data redacted] was too high.
The next 3 patients, receiving the revised D1 dose under this amended protocol, showed asymptomatic 
changes in HR (individual increases of 13-19, 13-22 and 9-28 BPM over baselines) and BP (individual 
systolic decreases: 12-13, 8-17 and 5-17 mmHg from baseline; individual diastolic decreases: 8-11, 14 and 
8-18 mmHg from baseline).  … [proprietary data redacted].  Patient-reported symptom assessments (scale 
0-65, see 6.3.1.3.) showed statistically signiﬁcant improvements in both symptom level and symptom 
volatility (individual pre-treatment means and standard deviations of 23.57±3.42, 43.91±3.48, 12.87±4.22 
decreasing to 15.97±2.21 37.00±3.28 8.11±4.17 post-treatment).  These changes are consistent with the 
postulate that up-regulated CRF2 in the limbic system increases the sensitivity to stressors and the release 
of 5HT (and other neurotransmitters) under stress, and thus down-regulating CRF2 will reduce symptom 
levels and volatility.  … [proprietary data redacted].  It would thus be beneﬁcial to understand the 
duration of infusion, in particular whether an additional 3.5-hour infusion will reduce symptom levels 
and volatility further (as previously contemplated in this protocol, section 6.3.1.5.3.).
To date, patients have been assessed by a variety of exploratory metrics including cardio-pulmonary 
exercise test (CPET) and cognitive scoring (via DANA mobile software).  CPET in particular was intended 
to be the primary endpoint in this trial.  However, the pre-treatment CPETs for all 5 patients do not 
indicate major patient deﬁcits relative to historical data for healthy subjects, and they do not exacerbate 
patient symptoms beyond normal day-to-day stressors.  Post-treatment CPETs for the 3 patients tested at 
the D1 dose show slight improvement in CPET parameters and reduced symptom exacerbation relative to 
pre-treatment exacerbation, but given the constraints that CPET imposes on the overall protocol (altitude, 
logistics, duration), such testing is not warranted for this essentially proof-of-concept trial.  Similarly, due 
to the lack of sensitivity to DANA cognitive testing, and the burden on subjects to complete these daily 
assessments, this test will no longer be performed.
Thus, the purpose of this amendment is to add an additional 3.5-hour infusion at the D1 dose, 
eliminate CPET testing (and associated visits to the clinic) and DANA testing, and to designate 
patient-reported symptom scores as the primary endpoint.
1.2.
Study Objectives
This study seeks to investigate the safety, tolerability and efﬁcacy of CT38 in the treatment of ME/CFS 
patients, based on the effect of CT38 on symptom levels (e.g., fatigue, pain, sleep, cognition, orthostatic 
intolerance, temperature, ﬂu-like, headaches or sensitivities, shortness of breath, gastrointestinal, 
urination, anxiety, depression), functional capacity (activity, sleep quality, energy expenditure, HR and 
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hours of upright activity), and general health status (global change, HR, BP, oral temperature, respiratory 
rate), pre- and post-treatment.
1.2.1.
Potential Risks
The principal risks associated with CT38 are a potential increase in HR and decrease in BP.  In the 
remainder of this trial, CT38 will be dosed via continuous SC infusion, repeated on 3 separate days.  The 
original protocol lowest dose-level was associated with increased HR and decreased BP.  The revised 
dosing utilizes lower rates of infusion and lower total doses.  To mitigate risks further, dosing will be 
sequential, commencing with the lowest dose group and escalating only in the absence of clinically 
important hemodynamic changes at the preceding dose-level.  HR and BP will be monitored during 
dosing and will have to remain within an acceptable range (see below), as a prerequisite for ascending to 
the next dose-level.
Beyond the investigational agent itself, there are minor risks associated with needle insertion, for blood 
sampling or drug administration.
1.2.2.
Potential Beneﬁts
If the hypothesized up-regulation of CRF2 is correct, and if the proposed treatment achieves CRF2 
endocytosis (as it likely does in rats—based upon the loss of the ability to induce effects mediated by 
CRF2 stimulation), the proposed treatment could reset the receptor within the raphe nuclei and limbic 
system to pre-ME/CFS levels.  This should reduce the sensitivity of the stress response, thereby reducing 
stress-induced symptom exacerbation.  If the receptor remains internalized, the treatment could be 
curative.
1.3.
Investigational Plan
1.3.1.
Study Design
1.3.1.1.
Overview
This study is a single-center, open-label, 18-patient, 3-arm Phase 1/2 clinical trial, to evaluate safety, 
tolerability and efﬁcacy of CT38, administered as the acetate salt CT38s, by the SC route of 
administration, at up to 3 separate dose-levels, for the treatment of ME/CFS.
The study is comprised of a recruitment and screening period, enrollment (Day 1), a 4-week pre-
treatment assessment period (Days 1-28), a 1-week interventional treatment period (Days 29-35) with 
drug infused on Days 29, 31 and 33, a 4-week post-treatment assessment period (Days 36-63), and a close-
out (Day 64).
1.3.1.2.
Primary Endpoint
The primary endpoint will be determined from a pre- and post treatment assessment of visual analog 
scale (VAS) scores recorded daily for each of 13 symptoms, namely:  (i) fatigue; (ii) muscle/joint pain; (iii) 
sleep problems, e.g., un-refreshing sleep, difﬁculty falling or staying asleep, excessive sleepiness; (iv) 
cognitive problems, e.g., slow information processing, memory difﬁculties, inability to concentrate/focus, 
attention deﬁcit; (v) orthostatic intolerance; (vi) body temperature perceptions; (vii) ﬂu-like symptoms, 
e.g., sore throat, tender lymph nodes, swollen glands, fever, chills, sinus/nasal problems; (viii) headaches 
or sensitivities to light, sound, smell, touch, taste; (ix) shortness of breath; (x) gastrointestinal problems, 
e.g., nausea, stomach/abdominal pain, diarrhea; (xi) urogenital problems, e.g., frequent urination, (xii) 
anxiety; and (xiii) depression.
1.3.1.3.
Secondary Endpoints
The study will also evaluate various secondary endpoints, compared across the pre- and post-treatment 
assessment periods, to determine treatment-related effects on activity and general health status.
Speciﬁc secondary endpoints, measured pre- and post-treatment, will include:
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•
An assessment of hours of upright activity, and any unusual exertion or stimulation, will be recorded 
at the same time each day (ideally 6-8pm).
•
Exploratory measures:  Assessed via Fitbit Charge 2™ (measuring activity, HR and derivative 
parameters including resting HR, sleep level/duration, activity level/duration, steps, calories and 
distance, monitored continuously and summarized daily).
•
Orthostatic intolerance (OI) will be assessed at Visits 1 and 6, via of measures of HR and BP and 
symptomatology, while in the supine, seated and standing positions.
•
General health status:  Assessed via the 36-Item Short Form Survey Instrument [McHorney 1994]), and 
vitals (measuring HR, BP, temperature, respiratory rate) at Visits 1-6.
1.3.1.4.
Dosing
CT38s solution will be delivered by continuous SC infusion, via a CME T34™ programmable syringe 
pump), at a ﬁxed concentration, with patient-speciﬁc dose volumes calculated to achieve the intended 
dose levels, speciﬁed in terms of μg/kg of body weight, or μg/kg/hour (Table 6.1).
1.3.1.4.1.
CT38s Concentration 
The prior Phase 1 study… [proprietary data redacted].
1.3.1.4.2.
Dose Levels 
Patients will be enrolled sequentially to receive either D1 or D2 doses, with at least 3 patients per dose 
group, and the remainder allocated determined by the tolerability to D1 and D2.  In each case, the total 
dose will be delivered in the form of an SC infusion at a constant rate of infusion maintained for a period 
of 3.5 hours (~2 half-lives).  This infusion dose will take place at Visit 3 (Day 29), Visit 4 (Day 31) and 
Visit4b, i.e., a total dose delivered over 10.5 hours.
Dosing will take place sequentially with all D1 testing taking place before D2 testing.  Barring any 
clinically meaningful concerns with the D1 arm, including PK assessments, the D2 arm is intended to 
achieve higher concentrations and exposures (Table 6.1).
1.3.1.5.
Dose Justiﬁcation
Safety and toxicology testing of CT38 in animals [IB, Section 4] and humans [IB, Section 5], showed that the 
principal AEs resulting from CRF2 stimulation were increased HR, decreased BP and decreased 
temperature.  In animals, these effects generally correlated with … [proprietary data redacted].
In rats, cardiovascular adjustments during stress are known to involve both CRF1 and CRF2 in the BNST 
(in the limbic system) [Oliveira 2015], while stress-induced changes in body temperature are known to occur in 
the hypothalamus [Vinkers 2010].  Thus, these data collectively suggest that infusions of CT38 can bring about 
some level of CRF2 endocytosis within the limbic system [IB, Section 4.1.1.4].  The data further suggest that 
CRF2 endocytosis… [proprietary data redacted].
The ﬁrst 5 ME/CFS patients dosed under this protocol (see 6.1.2.6.), conﬁrmed that the AEs were indeed 
hemodynamic, and that these occurred at substantially lower plasma concentrations than in healthy 
subjects (Phase 1).  This apparent sensitivity of ME/CFS patients suggests that these curves may be left-
shifted, and thus the amended doses seek to reduce the rate of CRF2 stimulation.
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Table 6.1:  Revised Dosing Schedule
Dose
Total 
Dose
(μg/kg)
Priming 
Bolus
(μg/kg)
Infusion Rate (μg/kg/h) / Duration (h)
Estimated* 
Cmax
(ng/ml)
Estimated* 
AUC
(ng.h/ml)
Comment
Initial
Escalation 1
Escalation 2
Low
0.80
0.00
0.20 / 0:45
0.22 / 0:45
0.24 / 2:00
[proprietary data 
redacted]
Complete
D1
0.11
0.00
0.03 / 0:45
0.03 / 0:45
0.03 / 2:00
No priming, no escalation
D2
0.35
0.00
0.10 / 0:45
0.10 / 0:45
0.10 / 2:00
No priming, no escalation
Cmax = maximum plasma concentration, at the end of dosing; AUC = total area under the plasma concentration-time curve. 
* Estimated based on modeling the Phase 1 trial, in which CT38s was administered by SC bolus only and the first 2 patients dosed under this trial by SC infusion

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Physician-Sponsored Investigational New Drug Application
1.3.1.5.1.
Low Dose 
The Low dose group (2 patients) received total doses of between 0.79 and 0.83 μg/kg at each Visit.  
Although this was below the MTDb determined in Phase 1, it was associated with clinically signiﬁcant 
hemodynamic AEs, and will not be tested further.
1.3.1.5.2.
D1 Dose 
The D1 dose group will receive a total dose of 0.11 μg/kg utilizing a constant infusion rate of 0.03 μg/kg/
hour, repeated on each of 3 treatment days.  Patients will be monitored for an additional 90 minutes (or 
more, as needed) after the end of infusion, before leaving the clinic.
The ﬁrst 3 patients receiving the D1 dose on each of 2 separate treatment days reached maximum plasma 
concentrations of… [proprietary data redacted], with no evidence of carryover from the ﬁrst treatment 
day to the second.  The plasma concentrations remain below the level where hemodynamic changes were 
evident in the ﬁrst 2 ME/CFS patients dosed… [proprietary data redacted].
1.3.1.5.3.
D2 Dose 
Escalation to the D2 dose group will take place provided safety and tolerability parameters for the D1 
dose group support the escalation.  The D2 dose group will receive a total dose of 0.35 μg/kg and utilize 
a constant infusion rate of 0.10 μg/kg/hour.  This is projected to reach maximum plasma concentrations 
of… [proprietary data redacted].  Patients will be monitored for an additional 90 minutes (or more, as 
needed) after the end of infusion, before leaving the clinic.
It is anticipated that the revised D1 and D2 doses will be sufﬁcient to characterize the safety, tolerability 
and dose-concentration relationship in ME/CFS patients.  However, it might be necessary to add an 
additional dose, longer dosing timeframes and/or up to an additional 2 days of dosing.  This will only be 
done following a comprehensive assessment of safety, tolerability, pharmacokinetics and efﬁcacy.
1.3.1.5.4.
Total Exposure 
Long-term efﬁcacy studies in various animal models of muscle wasting, dosed CT38 by continuous SC 
infusion (utilizing implanted osmotic minipumps) at doses of 100 μg/kg/day of body weight for up to 3 
months in rats (5 months in hamsters).  In rats, this achieved… [proprietary data redacted], with the 
tested animals displaying no obvious safety concerns and exhibiting robust muscle preservation.  The D2 
dosing paradigm is not projected to exceed total exposure of… [proprietary data redacted] …in humans 
per infusion, which is several orders of magnitude below those utilized in long-term animal efﬁcacy 
studies.  
1.3.1.6.
Dose Discontinuation
It is impossible to know the extent of any potential CRF2 up-regulation and the related left-shift of the 
hemodynamic dose-response curve in ME/CFS patients.  While the revised dosing paradigm is not 
expected to cause clinically important changes in HR or BP, these will be carefully monitored during the 
procedure.  Baseline HR and BP measures will be made in duplicate just prior to the infusion and 
represent Time Zero (See Section 6.3.3.2.5). The baseline HR and BP (systolic and diastolic) will consist of 
the average of the duplicate readings taken in the semi-recumbent position.  Dosing should be stopped in 
a given patient if any of the following are noted:  (i) a systolic BP ≤ 90 mmHg or a ≥ 20 mmHg decrease 
from baseline on 3 consecutive readings; (ii) a diastolic BP ≤ 50 mmHg or a decrease ≥ 15 mmHg from 
baseline on 3 consecutive readings; or (iii) a resting HR ≥ 120 BPM or ≤ 45 BPM.  If a patient’s baseline HR 
or BP meet the ‘stopping criteria’ at baseline, the infusion must not be administered.  The investigator 
should discuss with the medical monitor whether to bring the patient back for reassessment for study 
drug infusion.  The time window for reassessment should not be greater than 14 days.  If, after 
reassessment, the patient does not receive the Visit 3 infusion, then the patient should be discontinued 
from the study.
Lack of tolerability will be monitored in an individual patient by a careful review of the type, severity and 
frequency of toxicities, e.g., as described in the National Cancer Institute, Cancer Therapy Evaluation 
Program, Common Terminology Criteria for Adverse Events v3.0, 12Dec2003.  Furthermore, a decrease 
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from baseline in either systolic BP of ≥ 20 mmHg or diastolic BP of ≥ 15 mmHg, on 2 readings 30 minutes 
apart will be reviewed for clinical manifestations of lack of tolerability.
1.3.2.
Selection of Study Population
1.3.2.1.
Inclusion Criteria
Patients who meet all of the following criteria are eligible to participate in the study:
•
Provision of signed and dated informed consent form
•
Ability to read, understand and speak English
•
Living at an altitude between 3,500 and 5,500 feet above sea level for the past 1 year
•
Willing to perform an exercise test
•
Diagnosed with ME/CFS and meet the following 3 case deﬁnitions:  Fukuda Research Case 
Deﬁnition for CFS (1994), Revised Canadian Consensus Criteria for ME/CFS (2010) and the IOM 
Clinical Diagnostic Criteria for ME/CFS (2015)
•
Relatively stable state of illness for the individual patient over the past 3 months
•
Male or female, between the ages of 18 and 60 years old
•
Males or females of reproductive potential agree to remain abstinent or use (or have their partner 
use) 2 acceptable methods of contraception, starting from the time of informed consent through 28 
days after the last dose of study drug.  Acceptable methods of birth control during the study are 
intrauterine device, diaphragm with spermicide, contraceptive sponge, condom or vasectomy.  Oral 
contraceptive pills may not be used as the sole method of contraception because the effect of CT38 on 
the efﬁcacy of oral contraceptive pills has not yet been established
•
Stated willingness to comply with all study procedures and remain available for the study duration
•
Have mobile (smart) phone and access to the internet
A patient may be enrolled only once and may only receive the prescribed 2 days of study treatment once.
1.3.2.2.
Exclusion Criteria
A patient who meets any of the following criteria will be excluded from participation in this study: 
•
Alternate medical or psychiatric illness that could explain the ME/CFS symptoms
•
Active or uncontrolled co-morbidities which in the opinion of the PI may interfere with the ability of 
the patient to participate in the study.  Co-morbidities may include acute infection, Crohn’s disease, 
diabetes mellitus (Type 1 or Type 2, evidenced by a history of hemoglobin A1C > 7 at any time), 
Guillain-Barre syndrome, lupus, multiple sclerosis, myasthenia gravis, rheumatoid arthritis, or other 
such diseases that may be exclusionary.  Particularly conditions or medications that cause 
immunodeﬁciency or immunosuppression will be excluded.  Examples of such conditions can be 
found in the tables “Causes of Secondary Immunodeﬁciency” and “Some Drugs that Cause 
Immunosuppression” in the “Merck Manual”
•
Pregnancy, or while breast feeding.  Women should not be enrolled within 6 months of giving birth 
and within 3 months of cessation of breast feeding
•
A Body Mass Index > 35
•
Cigarette smoker or former smoker who has smoked within 6 months of the start of the study
•
Living at an altitude that is more than 1,000 feet (lower or higher) from the study site (which is 4,500 
feet above sea level)
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•
History of:
-
Major depression with psychotic or melancholic features before the diagnosis of ME/CFS, or 
active depression (major depression with psychotic or melancholic features) as determined by 
self-report
-
Untreated endocrine diagnoses including hypothyroidism (Hashimoto’s, etc.), Grave’s disease, 
adrenal insufﬁciency, hypogonadism (testosterone deﬁciency), diabetes mellitus or insipidus
-
Acute infection within the past 30 days
-
Within the last 3 years, any signiﬁcant head injury, e.g., concussion with loss of consciousness, 
brain surgery, an automobile accident with head/neck injury, other traumatic brain injury
-
A supra-ventricular tachycardia or ventricular tachycardia, e.g., atrial ﬁbrillation or ﬂutter, 
paroxysmal atrial ﬁbrillation, junctional tachycardia, ventricular tachycardia
-
Severe baseline hypotension deﬁned as rested sitting systolic BP < 100 mmHg or rested sitting 
diastolic BP < 60 mmHg.  Severe baseline tachycardia (HR > 100 bpm) or bradycardia (≤ 45 bpm).
-
Renal impairment based upon the local lab normal estimated glomerular ﬁltration rate (eGFR) 
(drug is cleared by passive renal ﬁltration)
-
Known hypersensitivity or clinically signiﬁcant allergies to… [proprietary data redacted] (both 
excipients in the drug product)
-
Substance abuse in the past 12 months as determined by self-report
•
Improvement in overall ME/CFS symptoms as a result of any treatment intervention in the past 3 
months
•
Current treatment with medications that interact with pathways involving:  (i) 5HT (e.g., selective 
5HT re-uptake inhibitors or SSRIs, 5HT and norepinephrine re-uptake inhibitors or SNRIs, tricyclic 
antidepressants, monoamine oxidase inhibitors, triptans); (ii) norepinephrine (e.g., adrenergic 
agonists or antagonists, norepinephrine re-uptake inhibitors, norepinephrine and dopamine re-
uptake inhibitors); (iii) dopamine (e.g., norepinephrine and dopamine re-uptake inhibitors); and (iv) 
cortisol (e.g., oral glucocorticoids, ﬂudrocortisone).  Prior withdrawal of medications, see Section 
6.3.4.7.
•
Prior treatment with
-
Short-term (< 2 weeks) antiviral or antibiotic medication or ﬂu shot within the past 4 weeks
-
Long-term (> 2 weeks) antiretrovirals within the past 12 months
-
Rituximab™ within 6 months
-
Any new prescription drug or herbal remedy within 2 weeks prior to the onset of the trial
•
Current participation in another clinical treatment trial
1.3.2.3.
Removal of Patients from the Study
Withdrawn patients are those who do not complete all evaluations and procedures outlined in the 
protocol because of one of the following:  an AE; signiﬁcant protocol deviation that, in the opinion of the 
PI, may compromise the study results; voluntary withdrawal; or withdrawal at the PI’s discretion.
If possible, any patient who is withdrawn from the study will have, at the time of withdrawal, all exit 
procedures performed (see below).  All clinically signiﬁcant ﬁndings will be followed until resolved to the 
satisfaction of the PI in consultation with the Medical Monitor.  If patients withdraw before or during 
treatment, the clinical team will seek to enroll additional patients.
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1.3.3.
Study Procedures
1.3.3.1.
Schedule of Events
The complete schedule of study procedures is presented in Table 6.2.  While efforts will be made to 
comply with the schedule of events and descriptions below, the precise timing may vary, except for Visit 
3, Visit 4 and Visit 4b, which each must be separated by at least 48 hours and no more than 96 hours.  The 
pre-treatment assessment period (between Visit 1 and Visit 3) and the post-treatment assessment period 
(between Visit 4b and Visit 6) should each be at least 4 weeks.
1.3.3.2.
Study Speciﬁc Procedures
1.3.3.2.1.
Visit 1 (Day 1) 
During the recruitment period up to 18 ME/CFS patients will be screened according to the inclusion/
exclusion criteria with the goal of enrolling 6 patients per dose-level.  Qualiﬁed patients will be invited to 
participate in the study.
At Visit 1, patient eligibility will be conﬁrmed and the following will be conducted:
•
Completed and signed Informed Consent Form
•
Medical history, including any information on the event that triggered ME/CFS, alcohol, tobacco or 
nicotine-containing product use, illicit drug use, etc.
•
Medication history, including prescription drug or herbal remedy within the past 3 months and non-
prescription drug or vitamin within the past 2 weeks
•
Physical examination, including height and weight
•
Vital signs, including HR, BP (measured twice after 5 minutes sitting), oral temperature, respiratory 
rate
•
Completed SF-36 (done prior to OI testing, see below)
•
Urine pregnancy/drug screen
•
Blood test (to establish eGFR, as well as standard chemistry panel and complete blood count).  If the 
following laboratory blood tests have not been done within 3 months of the screening visit (or the 
results are not available) then these blood tests should be ordered as well:  Lipid panel (T.Chol, HDL, 
LDL and TG), Total and Free Testosterone (males), ESR, CRP, Rheumatoid Factor, ANA, TSH and 
Free T4, Vitamin D 25-OH, Ferritin, Creatine Kinase, hemoglobin A1C, PSA (males).
•
OI testing:  Patients will lay supine for 5 minutes with HR and BP recorded in the last minute of 
supine rest.  Patients will then sit upright with legs hanging over the side of the bed for 1 minute, 
with HR, BP and any new symptoms developing during the seated position (e.g., dizziness, visual 
disturbances, palpitations) recorded at the end of the 1-minute period.  Patients will then stand for 10 
minutes near the bed and HR, BP and any new symptoms will be recorded at 2, 5 and 10 minutes 
post standing.  Ideally, HR should be monitored continuously with a pulse oximeter or other such 
device.  Patients developing any symptoms suggestive of hypotension at any stage, should be rested 
in either the seated or supine position.
Before leaving the clinic, patients will be assigned a patient number and Fitbit Charge 2™ for continuous 
monitoring (activity, sleep and HR) throughout the trial..
1.3.3.2.2.
Pre-Treatment Assessment Period (Days 1-28) 
In the 4-week pre-treatment assessment period, patients will utilize the wearable Fitbit Charge 2™ to 
record activity, sleep-related data and HR, and complete the daily VAS (online), and daily hours of 
upright activity (online).  Patients will also record any changes in medication use, any AEs and other 
qualitative observations (online).
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1.3.3.2.3.
Visit 3 (Day 29) 
At Visit 3 (Day 29) patients will complete SF-36 and undergo a brief physical exam, recording vitals and 
any patient-recorded changes in medications, AEs and other qualitative observations during the pre-
treatment recovery period.  A urine pregnancy test will be performed prior to study drug administration.  
In addition, patients will have an intravenous catheter placed in the arm to facilitate blood sampling for 
PK assessment. Following this, the study drug will be administered as outlined above, beginning at 
approximately 10am.
Patients should be semi-recumbent before and during the infusion procedure.  Prior to the infusion, 
duplicate measures of HR and BP should be made after 10 minutes in the semi-recumbent position. The 
duplicate measures should be averaged and the average of the HR, systolic and diastolic BP will 
represent baseline (Time Zero).  These baseline values should be recorded and the infusion stopping 
criteria (Section 6.3.1.6) should be annotated prior to the start of the infusion for reference purposes.  
During the procedure, HR and BP will be monitored every 15 minutes throughout the infusion period 
and for a minimum of 90 minutes post infusion.  The post infusion vital sign monitoring may be 
prolonged as appropriate until clinically stable.  PK samples will be obtained prior to the onset of study 
drug administration, and at 45 minutes, 90 minutes, 210 minutes (after stopping infusion) and at 300 
minutes (before the patient is allowed to go home).  All AEs will be assessed and recorded as well as the 
need for any medications.  Provided patients are clinically stable they may leave the clinic at 2 hours post-
infusion.
1.3.3.2.4.
Visit 4 (Day 31) 
At Visit 4 (Day 31) patients will undergo a brief physical exam, recording vitals and any patient-recorded 
changes in medications or AEs.  Following this, the study drug will be administered as outlined above 
(see Visit 3), beginning at approximately 10am.
Both before and during the infusion procedure, HR and BP will be monitored exactly as described for 
Visit 3, and blood samples for PK assessment will be obtained, per the schedule at Visit 3.  All AEs will be 
assessed and recorded as well as the need for any medications.
1.3.3.2.5.
Visit 4b (Day 33) 
At Visit 4b (Day 33) patients will undergo a brief physical exam, recording vitals and any patient-
recorded changes in medications or AEs.  Following this, the study drug will be administered as outlined 
above (see Visit 2), beginning at approximately 10am.
Both before and during the infusion procedure, HR and BP will be monitored exactly as described for 
Visit 3, and blood samples for PK assessment will be obtained, per the schedule at Visit 3.  All AEs will be 
assessed and recorded as well as the need for any medications.Treatment Period (Days 29-36)
Throughout the 1-week treatment period (including treatment days), patients will utilize the wearable 
Fitbit Charge 2™ to record activity, sleep-related data and HR, and complete the daily VAS (online), and 
daily hours of upright activity (online).  Patients will also record any changes in medication use, any AEs 
and other qualitative observations (online).
1.3.3.2.6.
Post-Treatment Assessment Period (Days 36-63) 
Throughout the 4-week post-treatment recovery period, patients will utilize the wearable Fitbit Charge 
2™ to record activity, HR and sleep-related data, and complete the daily VAS (online), and daily hours of 
upright activity (online).  Patients will also record any changes in medication use, any AEs and other 
qualitative observations (online).
1.3.3.2.7.
Visit 6 (Day 64) 
At Visit 6 (Day 64), patients will undergo a ﬁnal checkup, including physical examination, recording 
vitals and any updates to patient history.  Patient will be required to complete SF-36, followed by OI 
testing conducted exactly as at Visit 1.  All AEs will be assessed and recorded as well as the need for any 
medications.
1.3.3.3.
Safety Assessments
Speciﬁc safety parameters and procedures will be as follows:
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•
Clinical observation and assessment of AEs
•
Subjective symptoms and complaints via individual interviews
•
Vital signs, including HR, BP, oral temperature and respiratory rate.  Abnormal BP readings will be 
treated and followed as appropriate
•
Physical examination as required
When an AE is suspected, all relevant evaluations will be carried out and appropriate treatment 
provided.  Additional follow-up will be performed as necessary, recorded in the patient’s source 
documents, with the results provided to the PI.  Patients who experience any clinically signiﬁcant AE will 
remain under medical supervision until the PI, in consultation with the Medical Monitor, deems the AE to 
be resolved, stabilized, or no longer serious enough to warrant follow-up.
Note that prior to dose, only serious, procedure-related AEs will be captured on the AE case report form).  
For AE deﬁnitions and reporting requirements, see below.
1.3.4.
Study Agent
1.3.4.1.
Formulation, Appearance, Packaging, and Labeling
All study medication will be supplied by Cortene in sterile single-use vials.
CT38 Concentrate will be supplied in Schott 6R vials containing 1 ml of 1 mg/ml concentration… 
[proprietary data redacted].
Diluent for CT38 Concentrate will be supplied in Schott 6R vials containing 6 ml of… [proprietary data 
redacted].
1.3.4.2.
Product Storage and Stability
The unopened vials of CT38 Concentrate and Diluent for CT38 Concentrate are to be stored at -20ºC, 
which ensures at least 18 months of stability.
1.3.4.3.
Preparation
Prior to use, CT38 Concentrate must be diluted, using the Diluent for CT38 Concentrate, to produce the 
sterile solution intended for patient dosing (“CT38 Solution”)… [proprietary data redacted].
Following overnight thawing (at 5ºC)… [proprietary data redacted] …of respectively CT38 Concentrate 
and Diluent for CT38 Concentrate, are drawn into the syringe intended for patient dosing.  The resulting 
CT38 Solution for injection/infusion must be refrigerated at 5°C for no more than 24 hours prior to use.  
Detailed instructions will be provided to the site directly.
1.3.4.4.
Management of Clinical Supplies
The PI will have overall responsibility for the use of the study medication, and will not permit use other 
than as directed by this protocol.  The PI or designee will provide a signed acknowledgment for receipt of 
the study medications and a signed acknowledgment for return of study medication containers and 
unused study medication.
Qualiﬁed study center personnel must receive study drug deliveries, record the receipt, and assure that 
the study drug is handled and stored safely and properly.  The invoice must be reconciled against the 
vials received.  Any extra/damaged drug product vials will be destroyed at the study center as instructed 
and documented by Cortene.
A site designated person and a dedicated assistant, using the accompanying dosing instructions, will 
prepare doses for each patient.  Preparation must be documented and checked.  Copies of all invoices and 
dispensing records for the study drug must be kept at the study center as part of required study 
documentation.  At the end of the study, the study center must be able to reconcile delivery records with 
records of study drug received, dispensed and returned.  An account must be given of any discrepancies.  
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Upon completion or termination of the study, remaining drug substance and administration materials 
will be returned to Cortene, unless otherwise instructed by Cortene.
1.3.4.5.
Treatments Administered
Study drug will be administered as described above.  The site will prepare the doses using only materials 
provided by Cortene for this study.  Dosing solutions will be prepared using empty sterile syringes, 
according to the Dose Preparation Form instructions provided by Cortene.  All parenteral products will 
be inspected visually prior to administration.  The solution should be administered only if it is clear, 
colorless, and free of visible particulate matter.
1.3.4.6.
Treatment Compliance
The prescribed dosage and mode of administration may not be changed.  Any departures from the 
intended regimen will be recorded.
1.3.4.7.
Prior and Concomitant Therapy
During study participation, patients will be prohibited from taking any new prescription medications 
unless required to treat an emergency, or as explicitly approved by the PI and Medical Monitor.  
Examples of these drugs include amphetamines (e.g., Adderall, armodaﬁnil, modaﬁnil and 
methylphenidate).  Short acting benzodiazepines and gabapentin use are allowed.
Patients who have been withdrawn from medications that interact with the 5HT, norepinephrine or 
dopamine signaling pathways, should have been withdrawn at least 6 weeks prior to screening and 
should have had 4 weeks of relative stability prior to screening in the opinion of the investigator.  If 
patients have been recently withdrawn (at least 6 weeks) from oral corticosteroids, the investigator 
should be satisﬁed that the underlying illness for which these medications were used is stable and the 
risk of having to reinitiate the corticosteroids over the period of the trial is low.
1.3.5.
Statistical Methods
1.3.5.1.
Statistical Analysis Plan
Descriptive statistics such as means, medians, standard deviations, and interquartile ranges will be 
generated for all continuous variables, while frequency tables will be provided for categorical and 
discrete variables.  In addition, other exploratory statistical analyses, including stratiﬁcation for disease 
severity and other variables, will also be performed.  A signiﬁcance level (p-value) of less than 0.05 will be 
used for all statistical tests.
1.3.5.2.
Power and Sample Size Considerations
Given that this is a proof of concept study, no formal power calculations have been made.  The study 
seeks to enroll up to 18 patients.  Summary statistics will be performed with comparison made between 
pre- and post-treatment assessment periods using appropriate statistical tests.   
1.3.6.
Data Quality Assurance
The following steps will be taken to ensure the accuracy, consistency, completeness, and reliability of the 
data:
•
Site initiation call
•
Case report form review against source documents
•
Data management quality control checks
•
Statistical quality control checks
•
Continuous data acquisition and cleaning
•
Internal review of data
•
Quality control check of the ﬁnal report
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1.4.
Investigator’s Obligations
This study will be conducted in accordance with this protocol, the International Conference on 
Harmonization (ICH) Harmonized Tripartite Guideline for Good Clinical Practice, 1997, the US Code of 
Federal Regulations Title 21 parts 50, 56, and 312, and the ethical principles that have their origin in the 
Declaration of Helsinki.
1.4.1.
Institutional Review
The PI will not begin the study until the protocol and informed consent form have been approved by the 
Institutional Review Board (IRB).  The IRB will also review and approve all advertisements.  The IRB’s 
approval will be documented in writing and sent to the PI.  The PI will forward a copy of the IRB 
approval document to Cortene.  Any amendments to the protocol must also be approved in writing by 
the IRB, prior to implementation by the PI, except where necessary to eliminate an immediate hazard to 
study patients.
1.4.2.
Patient Consent
Each patient must sign and personally date a study-speciﬁc informed consent form to participate in the 
study.  This consent form will comply with all applicable regulations governing the protection of human 
patients.  The basic elements of informed consent are speciﬁed in the US Code of Federal Regulations 
Title 21 parts 50.25 and 50.27, and the ICH Harmonized Tripartite Guideline for Good Clinical Practice.
The PI will obtain the IRB’s written approval of the written informed consent form to be provided to the 
patients, including approval of all revisions.  Prior to the start of the study, the PI or an authorized staff 
member will inform patients about the nature of the study.  Patients will have the opportunity to inquire 
about details of the study and to decide whether to participate.  Patients will be instructed that they are 
free to withdraw their participation in the study at any time without penalty or loss of beneﬁts to which 
they are otherwise entitled.  The PI will inform patients of new information that may be relevant to the 
patients’ willingness to continue participation in the study.
The PI will provide each patient with a copy of the signed and dated consent form and will document in 
the patient’s source documents that informed consent was given.
1.4.3.
Data Collection
1.4.3.1.
Case Report Forms
This study will utilize online case report forms (using REDCap).
1.4.3.2.
Source Documents
The PI will prepare and maintain adequate and accurate source documents (medical records, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each patient treated 
with the study drug.
The PI will allow Cortene representatives, contract designees, and authorized regulatory authority 
inspectors to have direct access to all documents pertaining to the study.
1.4.4.
Adherence to Protocol
By signing the Protocol Approval Signature Page of this protocol, the PI conﬁrms in writing that he/she 
has read, understands, and will strictly adhere to the study protocol and will conduct the study in 
accordance with ICH Harmonized Tripartite Guidelines for Good Clinical Practice and applicable 
regulatory requirements.
1.4.5.
Reporting Adverse Events
1.4.5.1.
Safety Deﬁnitions
AE:  Any unfavorable or unintended sign, symptom, or disease that appears or worsens in a patient 
during the period of observation in a clinical study.  The AE may be any of the following:
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•
A new illness
•
An exacerbation of a sign or symptom of the underlying condition under treatment or of a 
concomitant illness, unrelated to participation in the clinical study, or an effect of the study 
medication
•
A combination of one or more of the above factors
No causal relationship with the study medication is implied by the use of the term “adverse event.”  An 
exacerbation of a pre-existing condition/illness is deﬁned as a more frequent occurrence or as an increase 
in the severity of the pre-existing condition/illness during the study.  Planned or elective surgical or 
invasive procedures for pre-existing conditions that have not worsened are not AEs.  However, any 
complication that occurs during a planned or elective surgery is an AE.  (If the event ﬁts the serious 
criteria, such as an extended hospitalization, it will be considered an SAE.)  Conditions leading to 
unplanned surgical procedures may be AEs.
When an AE occurs after written informed consent has been obtained but before the ﬁrst dose of study 
drug, the AE will be considered a non-treatment-emergent AE.  Only serious non-treatment-emergent 
AEs that are related to study procedures will be collected.  An AE that occurs from the time the patient 
receives his/her ﬁrst dose of study drug until his/her exit from the study will be considered a treatment-
emergent AE.  All treatment-emergent AEs will be collected.
Immediately Reportable Adverse Event (IRAE) include all SAEs (as listed below), AEs that result in a 
patient’s withdrawal from the study, and designated program-speciﬁc AEs, and must be reported to 
Cortene within 24 hours of the study center being informed. 
SAE:  As provided by the ICH criteria, any AE that:
•
results in death
•
is life threatening (Note, the term "life threatening" refers to any AE that, as it occurs, puts the patient 
at immediate risk of death.  It does not refer to an AE that hypothetically might have caused death if 
it were more severe).
•
results in hospitalization or prolongation of current hospitalization (not including hospitalization for 
a pre-existing condition that has not increased in severity or frequency from the patient's underlying 
medical condition prior to entry into the study)
•
results in persistent or signiﬁcant disability/incapacity
•
is a congenital anomaly/birth defect in the offspring of a patient
•
is judged to be medically signiﬁcant (Note, a medically signiﬁcant AE is a medical event that may not 
be immediately life-threatening or result in death or hospitalization, but may jeopardize the patient 
or require intervention to prevent one of the outcomes listed above.  Medical and scientiﬁc judgment 
should be exercised in deciding whether other AEs appropriately meet these criteria and are 
immediately reportable to Cortene.  Examples of such medical events include allergic bronchospasm 
that requires intensive treatment in an emergency room or at home and blood dyscrasias or 
convulsions that do not result in in-patient hospitalization).
When completing appropriate forms for reporting the AE, the PI will be asked to assess the AE as follows:
Severity of AE:  Refers to the extent to which an AE affects the patient’s daily activities.  Severity will be 
categorized according to the following criteria:
•
Mild:  Normal activities unaltered 
•
Moderate:  Normal activities altered
•
Severe:  Unable to undertake normal activities.
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The term “severity” is used to describe the intensity of an event (as in mild, moderate, severe); the event 
itself may be of relatively minor medical signiﬁcance, such as a severe headache.  This is not the same as 
“serious.”  Seriousness, not severity, serves as the guide for deﬁning regulatory reporting obligations.
Causality of AE:  Refers to the relationship of the AE to study drug.  Causality will be categorized 
according to the following criteria:
•
Doubtful:  There is no medical evidence to suggest that the AE may be related to study drug usage, 
or there is another more probable medical explanation
•
Possible:  There is medical evidence to suggest that the AE may be related to study drug usage.  
However, other medical explanations cannot be excluded as a possible cause
•
Probable:  There is strong medical evidence to suggest that the AE is related to study drug usage
1.4.5.2.
Reporting Forms
In this study AEs will be reported via the case report form.
All AEs (AE log of case report form):  The AE log is part of the case report form and is used to collect 
information on the following:
•
All treatment-emergent AEs (serious and non-serious)
•
Serious, non-treatment-emergent AEs related to study procedures
Every attempt should be made to describe the AE in terms of a diagnosis.  If a clear diagnosis has been 
made, individual signs and symptoms will not be recorded unless they represent atypical or extreme 
manifestations of the diagnosis, in which case they should be reported as separate events.  If a clear 
diagnosis cannot be established, each sign and symptom must be recorded individually.
IRAEs:  All known information regarding the IRAE must be recorded on the AE log of the case report 
form and all other case report forms updated or completed as necessary.  Case report forms that must be 
completed for all IRAEs are:  patient accountability, study drug accountability, demographics, medical 
history, and concomitant medications.  This information must be completed within 24 hours of the study 
center being informed of the IRAE.
1.4.5.3.
Adverse Event Reporting Contacts
For questions regarding IRAEs, or to notify Cortene of an IRAE in the event of technical failure, the PI 
should contact the Medical Monitor.
1.4.5.4.
Unintended Pregnancy
Patients will be instructed to notify the investigator if they become pregnant at any time during the study, 
or if they become pregnant within 30 days of last study drug dose.  Patients who become pregnant or 
who suspect that they are pregnant during the study must report the information to the PI and 
discontinue study drug immediately.  Patients whose partner has become pregnant or suspects she is 
pregnant during the study must report the information to the investigator.
The study consent allows the PI to follow a patient or partner pregnancy until completion or termination.  
The patient will be asked to provide information on the outcome of their or partner pregnancy, including 
early termination.  The PI or study staff may share this information with Cortene and the IRB.
1.4.6.
Records Retention
The PI must maintain essential study documents (protocol and amendments, source documentation 
corresponding to all information contained in the case report form, signed informed consent forms, 
relevant correspondence, test results, and all other supporting documentation) until at least 2 years after 
the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years after the formal discontinuation 
of clinical development of the investigational product.  These documents should be retained for a longer 
period if required by the applicable regulatory requirements or the hospital, institution, or private 
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practice in which the study is being conducted.  Patient identiﬁcation codes (patient names and 
corresponding study numbers) will be retained for this same time period.  Custody of the records may be 
transferred to another responsible party, acceptable to Cortene, who agrees to abide by the retention 
policies.  Written notice of transfer must be submitted to Cortene.  The PI must contact Cortene prior to 
disposing of any study records.
1.4.7.
Publications
The PI agrees that all data, calculations, interpretations, opinions, and recommendations regarding the 
study will be the property of Cortene.  The PI agrees to consider the results as information subject to 
conﬁdentiality and use restrictions.
1.5.
Study Administration
1.5.1.
Management of Protocol Amendments and Deviations
With the exception of an emergency situation, implementation of any change in the protocol that affects 
the safety of the patients, the scope of the investigation, or the scientiﬁc quality of the study will not be 
permitted until Cortene, the PI and the IRB responsible for review and approval of the study have 
reviewed and approved the amendment.
Implementation of changes that do not affect the safety of the patients, the scope of the investigation, or 
the scientiﬁc quality of the study cannot be made until the protocol changes are reviewed and approved 
by Cortene and the PI.  The IRB must be notiﬁed of these protocol changes.
The PI will not deviate from the protocol without prior written approval from Cortene.  In the event of an 
emergency, the PI shall implement any medical procedures deemed appropriate.  However, all such 
procedures must have written documentation and be promptly reported to Cortene.
1.5.2.
Study Termination
This study may be temporarily suspended or prematurely terminated if there is sufﬁcient reasonable 
cause.  Written notiﬁcation, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the FDA.  If the study is prematurely terminated or 
suspended, the PI will promptly inform the IRB and will provide the reason(s) for the termination or 
suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
•
Determination of unexpected, signiﬁcant, or unacceptable risk to patients 
•
Demonstration of efﬁcacy that would warrant stopping 
•
Insufﬁcient compliance to protocol requirements 
•
Data that are not sufﬁciently complete and/or evaluable 
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy PI, IRB and FDA.
The study is considered terminated upon completion of all patient treatments and evaluations.
1.5.3.
Final Report
The PI will review and sign the ﬁnal report at the conclusion of this clinical study.
1.5.4.
Patient-Related
1.5.4.1.
Patient Identiﬁcation
Upon their enrollment in the study, all patients will be assigned a unique study number.  The link 
between the patient’s study number and their identiﬁers will be kept in a password-protected database 
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that only the study team can access, in compliance with the Health Insurance Portability and 
Accountability Act of 1996.
1.5.4.2.
Patient Payments
Patients will be compensated for their time at a rate of US$10/hour, for parking and transportation at 
US$10/visit (5 separate study visits).  Patients’ time will include screening/enrollment at Visit 1 (4 hours), 
treatment at Visit 3, Visit 4 and Visit 4b (each 7 hours), close-out at Visit 6 (2 hours), and data entry over 
the course of the study (18 hours), so a total of 45 hours.  This amounts to a total compensation of $500 
provided all study visits and outcome measures are completed, which will be paid after the completion of 
the Visit 6.  Patients only completing through Visit 1, Visit 3, Visit 4 and Visit 4b will receive respective 
payments of $50, $150, $250 and $350 in total.
1.5.4.3.
Insurance
If health complications due to study procedures arise, the PI and the research study staff will assist the 
patient in obtaining appropriate medical treatment.  In the event that the patient has an injury or illness 
that is directly caused by his or her participation in this study, reimbursement for medical expenses (e.g., 
ambulance, hospital, professional nursing, dental, medical, surgical, imaging, ﬁrst aid and funeral 
services) will be sought from Cortene’s insurer.
If the patient’s medical expenses related to such an injury are not covered by Cortene’s insurer, the 
patients may be responsible for these costs.
1.5.4.4.
Strategies for Recruitment and Retention
The study will seek to recruit a total of 18 ME/CFS patients within Salt Lake City and the surrounding 
areas.
Potential cases will be identiﬁed/recruited as follows.
•
PI’s current and prior ME/CFS patients may be eligible for the study.  PI will generate a list of male 
and female patients who are between ages 18 and 60.  These patients will be called on the telephone 
to determine interest in participating in the study, and if interested, will be screened for eligibility, 
and if eligible, invited to schedule the ﬁrst study visit.
•
PI’s waiting list of ME/CFS patients will be called, and if interested, will be screened for eligibility, 
and if eligible, invited to schedule the ﬁrst study visit.  
•
Study ﬂyers will be posted at PI’s clinic with the research coordinator’s contact information.  Patients 
who call will be screened for eligibility, and if eligible, invited to schedule the ﬁrst study visit.
•
Advertisements for the study will be posted on the Bateman Horne Center’s website.  Potential 
patients who contact the research coordinator will be screened for eligibility, and if eligible, invited to 
schedule the ﬁrst study visit.
•
The study team will also contact other providers who see ME/CFS patients.  Such providers may 
refer patients to the study and may also post the study ﬂyers in their ofﬁces and advertisements on 
their websites.  Interested patients who contact the research coordinator will be screened for 
eligibility, and if eligible, invited to schedule the ﬁrst study visit.  
•
Patients will also be recruited using the website ResearchMatch, a registry with over 79,000 patients, 
created by the Clinical & Translational Science Awards (CTSA) Consortium and funded by the 
National Center for Research Resources.  Once recruitment access has been approved by the site 
(with evidence of IRB-study approval), the research coordinator will search for matches among the 
patient proﬁles within the system and send a recruitment message to potential matches through 
ResearchMatch.  For those patients who authorize ResearchMatch to release their contact 
information, the research coordinator will contact the patient to set up a telephone screening. Such 
patients will be screened for eligibility, and if eligible, invited to schedule the ﬁrst study visit.
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