InTiME: Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

• Sponsor: LUCINDA BATEMAN, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT03613129
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arms: 4
• Actual Duration (Months): 9.2
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

This study seeks to investigate the safety, tolerability and efficacy of CT38, an experimental peptide administered by subcutaneous infusion, in the treatment of ME/CFS patients.

Condition or Disease	Intervention/Treatment	Phase
Myalgic Encephalomyelitis; Chronic Fatigue Syndrome	Drug: CT38	Phase 1/Phase 2

Detailed Description

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) 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. Patients are often unable to handle the activities of daily living and experience a loss of career and a very poor quality of life. There are no established diagnostic tests or approved therapeutics for ME/CFS.

The cause of ME/CFS is not known. It has been postulated that ME/CFS could arise from the up-regulation of a specific receptor (CRF2) in those parts of the brain that govern the sensitivity of the stress response. This configuration would invoke a major response to a minor stimulus, ultimately leading to neuroendocrine, autonomic, immune and metabolic abnormalities that are commonly observed. There is no animal model of ME/CFS, but overstimulating CRF2 in healthy rats, induces signs and symptoms consistent with the disease in humans; while down-regulating it, via CT38 (an experimental peptide), eliminates the ability to stimulate these signs and symptoms. Hypothesis: Utilize CT38 to down-regulate CRF2 to restore a normal stress response, and potentially eliminate disease signs and symptoms.

The study will enroll 18 patients, who meet the Fukuda and Canadian criteria for ME/CFS, and treat them with various doses of CT38.

The primary endpoint will be the change in the average total daily symptom score (TDSS), over 28-day periods immediately prior to the first treatment (pre-treatment) and immediately prior to exit from the trial (post-treatment). The TDSS is the sum of 13 individual symptom scores, each recorded daily by the patient on a 6-point scale (0=none, 1=very mild, 2=mild, 3=moderate, 4=severe, 5=very severe). The individual symptoms included fatigue, muscle/joint pain, sleep issues (e.g., un-refreshing sleep, difficulty falling or staying asleep, excessive sleepiness), cognitive issues (e.g., slow information processing, memory difficulties, inability to concentrate/focus, attention deficit), orthostatic intolerance (e.g., dizziness, spatial disorientation, light-headedness, feeling faint), body temperature perceptions, flu-like symptoms (e.g., sore throat, tender lymph nodes, swollen glands, fever, chills, sinus/nasal problems), headaches or sensory sensitivities (to light, sound, smell, touch, taste), shortness of breath, gastrointestinal problems (e.g., nausea, stomach/abdominal pain, diarrhea), urogenital problems (e.g., frequent urination), anxiety and depression.

The secondary outcomes will assess general health status (determined by Short-Form 36, or SF-36), as well as safety assessments.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: The study is comprised of a recruitment and screening period, enrollment (Visit 1), a 4-week (at least) pre-treatment assessment period, a 1-week interventional treatment period with drug infused at Visits 3, 4 and 4b, a 4-week (at least) post-treatment assessment period, and a close-out (Visit 6).The study is comprised of a recruitment and screening period, enrollment (Visit 1), a 4-week (at least) pre-treatment assessment period, a 1-week interventional treatment period with drug infused at Visits 3, 4 and 4b, a 4-week (at least) post-treatment assessment period, and a close-out (Visit 6).
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Phase 1/2, Open-Label, Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
• Actual Study Start Date: Jul 23, 2018
• Actual Primary Completion Date: Apr 30, 2019
• Actual Study Completion Date: Apr 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: D0.20 Subcutaneous infusion of CT38 at 0.20 μg/kg/hour, for 3 hours on each of 2 days	Drug: CT38; Infusion
Active Comparator: D0.03 Subcutaneous infusion of CT38 at 0.03 μg/kg/hour, for 3.5 hours on each of 3 days	Drug: CT38; Infusion
Active Comparator: D0.06 Subcutaneous infusion of CT38 at 0.06 μg/kg/hour, for 3.5 hours on each of 3 days	Drug: CT38; Infusion
Active Comparator: D0.01 Subcutaneous infusion of CT38 at 0.01 μg/kg/hour, for 3.5 hours on each of 3 days	Drug: CT38; Infusion

Outcome Measures

Primary Outcome Measures

1. Total Daily Symptom Score (TDSS) [28 days preceding Visit 3 (pre-treatment) and 28 days preceding Visit 6 (post-treatment)]

   Pre-/post-treatment difference in TDSS (0-65 scale, 0=no symptoms; 65=maximum of 5 for each of 13 specific patient-reported symptoms). The TDSS sums the patient-reported daily symptom score for each of 13 specific symptoms (including fatigue, muscle/joint pain, sleep problems, cognitive problems, orthostatic intolerance, body temperature perceptions, flu-like symptoms, headaches or sensitivities, shortness of breath, gastrointestinal problems, urogenital problems, anxiety and depression), each assessed on a 0-5 scale (0=no symptom, 1=very mild, 2=mild, 3=moderate, 4=severe, 5=severe)

Secondary Outcome Measures

1. SF-36, PCS [Visit 3 before treatment (pre-treatment) and at Visit 6 (post-treatment)]

   Pre-/post-treatment difference in the physical component score (PCS) of the RAND 36-Item Health Survey (SF-36), on a 0-100 scale (where 0=max disability and 100=no disability)

2. SF-36, MCS [Visit 3 before treatment (pre-treatment) and at Visit 6 (post-treatment)]

   Pre-/post-treatment difference in the mental component score (MCS) of the RAND 36-Item Health Survey (SF-36), on a 0-100 scale (where 0=max disability and 100=no disability)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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 Institute of Medicine (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

Exclusion Criteria:

• Alternate medical or psychiatric illness that could explain the ME/CFS symptoms

• Unwilling or unable to perform an exercise test

• 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 glycated 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)

• 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

• 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 tromethamine or Tween 80 (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) 5-hydroxytryptamine (5HT) (e.g., selective 5HT re-uptake inhibitors or selective serotonin reuptake inhibitors (SSRIs), 5HT and norepinephrine re-uptake inhibitors or serotonin and norepinephrine reuptake inhibitors (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 pathways (e.g., oral glucocorticoids, fludrocortisone).

• 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

• RituximabTM 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bateman Horne Center	Salt Lake City	Utah	United States	84102

Sponsors and Collaborators

• LUCINDA BATEMAN, MD

Investigators

• Principal Investigator: Lucinda Bateman, MD, Bateman Horne Center
• Study Director: Suzanne D Vernon, PhD, Bateman Horne Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 7, 2018

More Information

Publications

None provided.

• Responsible Party: LUCINDA BATEMAN, MD, Founder & Medical Director, Bateman Horne Center
• ClinicalTrials.gov Identifier: NCT03613129
• Other Study ID Numbers: ME-101p
• First Posted: Aug 2, 2018
• Last Update Posted: May 12, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by LUCINDA BATEMAN, MD, Founder & Medical Director, Bateman Horne Center: myalgic encephalomyelitis; chronic fatigue syndrome; corticotropin releasing-factor receptor subtype 2 (CRF2); Alternative CRF2 names: CRFR2, CRH2, CRHR2
• Additional relevant MeSH terms: Fatigue Syndrome, Chronic; Encephalomyelitis; Myalgia; Syndrome; Fatigue

Study Results

Participant Flow

Arm/Group Title	Screen Failures	D0.01	D0.03	D0.06	D0.20
Arm/Group Description	Patient enrolled, but screened-out before receiving treatment	Subcutaneous infusion of CT38 at 0.01 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.03 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.06 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.20 μg/kg/hour, for 3 hours on each of 2 days
Period Title: Pre-treatment Assessment
STARTED	3	3	7	2	2
COMPLETED	0	3	7	2	2
NOT COMPLETED	3	0	0	0	0
Period Title: Pre-treatment Assessment
STARTED	0	3	7	2	2
COMPLETED	0	3	7	2	2
NOT COMPLETED	0	0	0	0	0
Period Title: Pre-treatment Assessment
STARTED	0	3	7	2	2
COMPLETED	0	3	7	2	2
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	D0.01	D0.03	D0.06	D0.20	Total
Arm/Group Description	Subcutaneous infusion of CT38 at 0.01 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.03 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.06 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.20 μg/kg/hour, for 3 hours on each of 2 days	Total of all reporting groups
Overall Participants	3	7	2	2	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.0 (8.2)	39.7 (7.2)	53.6 (0.6)	44.6 (21.4)	43.7 (9.7)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	5 71.4%	2 100%	0 0%	8 57.1%
Male	2 66.7%	2 28.6%	0 0%	2 100%	6 42.9%
Race/Ethnicity, Customized (Count of Participants)
White	3 100%	5 71.4%	2 100%	2 100%	12 85.7%
Other	0 0%	2 28.6%	0 0%	0 0%	2 14.3%
Age, at diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.7 (12.2)	32.4 (10.4)	46.0 (9.9)	32.5 (24.7)	34.6 (12.3)
Disease onset (Count of Participants)
Gradual	2 66.7%	3 42.9%	1 50%	2 100%	8 57.1%
Sudden	1 33.3%	4 57.1%	1 50%	0 0%	6 42.9%
Disease triggers (Count of Participants)
Infection	3 100%	6 85.7%	2 100%	2 100%	13 92.9%
Toxins	1 33.3%	2 28.6%	0 0%	1 50%	4 28.6%
Over-exertion	0 0%	1 14.3%	1 50%	0 0%	2 14.3%
Emotion	0 0%	3 42.9%	0 0%	1 50%	4 28.6%

Outcome Measures

1. Primary Outcome

Title	Total Daily Symptom Score (TDSS)
Description	Pre-/post-treatment difference in TDSS (0-65 scale, 0=no symptoms; 65=maximum of 5 for each of 13 specific patient-reported symptoms). The TDSS sums the patient-reported daily symptom score for each of 13 specific symptoms (including fatigue, muscle/joint pain, sleep problems, cognitive problems, orthostatic intolerance, body temperature perceptions, flu-like symptoms, headaches or sensitivities, shortness of breath, gastrointestinal problems, urogenital problems, anxiety and depression), each assessed on a 0-5 scale (0=no symptom, 1=very mild, 2=mild, 3=moderate, 4=severe, 5=severe)
Time Frame	28 days preceding Visit 3 (pre-treatment) and 28 days preceding Visit 6 (post-treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intent-to-treat	D0.01	D0.03	D0.06	D0.20
Arm/Group Description	All patients receiving test drug	Subcutaneous infusion of CT38 at 0.01 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.03 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.06 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.20 μg/kg/hour, for 3 hours on each of 2 days
Measure Participants	14	3	7	2	2
Pre-treatment TDSS	29.5 (9.4)	28.7 (12.2)	29.2 (11.4)	31.3 (1.3)	30.1 (8.0)
Post-treatment TDSS	25.3 (9.6)	25.5 (10.5)	21.7 (10.3)	29.5 (3.5)	33.0 (9.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intent-to-treat
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing 28-day pre-treatment mean TDSS and 28-day post-treatment mean TDSS
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	D0.01
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing 28-day pre-treatment mean TDSS and 28-day post-treatment mean TDSS
Statistical Test of Hypothesis	p-Value	0.136
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	D0.03
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing 28-day pre-treatment mean TDSS and 28-day post-treatment mean TDSS
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	D0.06
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing 28-day pre-treatment mean TDSS and 28-day post-treatment mean TDSS
Statistical Test of Hypothesis	p-Value	0.451
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	D0.20
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing 28-day pre-treatment mean TDSS and 28-day post-treatment mean TDSS
Statistical Test of Hypothesis	p-Value	0.240
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	SF-36, PCS
Description	Pre-/post-treatment difference in the physical component score (PCS) of the RAND 36-Item Health Survey (SF-36), on a 0-100 scale (where 0=max disability and 100=no disability)
Time Frame	Visit 3 before treatment (pre-treatment) and at Visit 6 (post-treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intent-to-treat	D0.01	D0.03	D0.06	D0.20
Arm/Group Description	All patients receiving test drug	Subcutaneous infusion of CT38 at 0.01 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.03 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.06 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.20 μg/kg/hour, for 3 hours on each of 2 days
Measure Participants	14	3	7	2	2
Pre-treatment PCS	27.9 (4.0)	25.9 (6.9)	24.6 (3.7)	27.6 (1.4)	30.6 (1.4)
Post-treatment PCS	31.5 (5.8)	29.1 (6.0)	30.7 (5.3)	27.0 (1.4)	26.8 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intent-to-treat
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment PCS (at Visit 3) and post-treatment PCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	D0.01
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment PCS (at Visit 3) and post-treatment PCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.191
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	D0.03
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment PCS (at Visit 3) and post-treatment PCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	D0.06
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment PCS (at Visit 3) and post-treatment PCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	D0.20
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment PCS (at Visit 3) and post-treatment PCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.060
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	SF-36, MCS
Description	Pre-/post-treatment difference in the mental component score (MCS) of the RAND 36-Item Health Survey (SF-36), on a 0-100 scale (where 0=max disability and 100=no disability)
Time Frame	Visit 3 before treatment (pre-treatment) and at Visit 6 (post-treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intent-to-treat	D0.01	D0.03	D0.06	D0.20
Arm/Group Description	All patients receiving test drug	Subcutaneous infusion of CT38 at 0.01 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.03 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.06 μg/kg/hour, for 3.5 hours on each of 3 days	Subcutaneous infusion of CT38 at 0.20 μg/kg/hour, for 3 hours on each of 2 days
Measure Participants	14	3	7	2	2
Pre-treatment MCS	34.0 (3.6)	36.3 (3.2)	28.9 (3.9)	32.1 (3.2)	35.8 (2.6)
Post-treatment MCS	34.8 (6.3)	38.5 (9.1)	29.9 (6.4)	34.9 (5.6)	31.5 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intent-to-treat
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment MCS (at Visit 3) and post-treatment MCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.587
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	D0.01
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment MCS (at Visit 3) and post-treatment MCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.618
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	D0.03
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment MCS (at Visit 3) and post-treatment MCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.634
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	D0.06
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment MCS (at Visit 3) and post-treatment MCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.355
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	D0.20
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Comparing pre-treatment MCS (at Visit 3) and post-treatment MCS (at Visit 6)
Statistical Test of Hypothesis	p-Value	0.417
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	At least 10 weeks
Arm/Group Title	Intent-to-treat		D0.01		D0.03		D0.06		D0.20
Arm/Group Description	All patients receiving test drug		Subcutaneous infusion of CT38 at 0.01 μg/kg/hour, for 3.5 hours on each of 3 days		Subcutaneous infusion of CT38 at 0.03 μg/kg/hour, for 3.5 hours on each of 3 days		Subcutaneous infusion of CT38 at 0.06 μg/kg/hour, for 3.5 hours on each of 3 days		Subcutaneous infusion of CT38 at 0.20 μg/kg/hour, for 3 hours on each of 2 days
All Cause Mortality
	Intent-to-treat		D0.01		D0.03		D0.06		D0.20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/3 (0%)		0/7 (0%)		0/2 (0%)		0/2 (0%)
Serious Adverse Events
	Intent-to-treat		D0.01		D0.03		D0.06		D0.20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)		0/3 (0%)		0/7 (0%)		0/2 (0%)		1/2 (50%)
Cardiac disorders
Tachycardia	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/2 (50%)	1
Vascular disorders
Hypotension	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Intent-to-treat		D0.01		D0.03		D0.06		D0.20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		3/3 (100%)		7/7 (100%)		2/2 (100%)		2/2 (100%)
Blood and lymphatic system disorders
Swollen lymph nodes	1/14 (7.1%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/2 (0%)	0	0/2 (0%)	0
Cardiac disorders
Palpitations	2/14 (14.3%)	5	0/3 (0%)	0	1/7 (14.3%)	3	1/2 (50%)	2	0/2 (0%)	0
Premature ventricular contraction	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Tachycardia	2/14 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	2/2 (100%)	2
Ear and labyrinth disorders
Tinnitus	1/14 (7.1%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/2 (0%)	0	0/2 (0%)	0
Eye disorders
Conjunctivitis	1/14 (7.1%)	2	0/3 (0%)	0	0/7 (0%)	0	1/2 (50%)	2	0/2 (0%)	0
Hyperemic eyes	1/14 (7.1%)	2	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/2 (50%)	2
Gastrointestinal disorders
Constipation	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Diarrhea	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/2 (50%)	1
Inflammatory bowel disease	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/2 (0%)	0
Nausea	3/14 (21.4%)	4	0/3 (0%)	0	3/7 (42.9%)	4	0/2 (0%)	0	0/2 (0%)	0
Sore throat	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
General disorders
Asthenia	1/14 (7.1%)	2	0/3 (0%)	0	1/7 (14.3%)	2	0/2 (0%)	0	0/2 (0%)	0
Body aches	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Body temperature abnormalities	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/2 (0%)	0
Fatigue	5/14 (35.7%)	10	0/3 (0%)	0	3/7 (42.9%)	5	0/2 (0%)	0	2/2 (100%)	5
Influenza like illness	3/14 (21.4%)	3	1/3 (33.3%)	1	1/7 (14.3%)	1	0/2 (0%)	0	1/2 (50%)	1
Malaise	1/14 (7.1%)	2	0/3 (0%)	0	0/7 (0%)	0	1/2 (50%)	2	0/2 (0%)	0
Myalgia	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/2 (0%)	0
Pain & discomfort	1/14 (7.1%)	2	0/3 (0%)	0	1/7 (14.3%)	2	0/2 (0%)	0	0/2 (0%)	0
Pyrexia	2/14 (14.3%)	2	0/3 (0%)	0	1/7 (14.3%)	1	1/2 (50%)	1	0/2 (0%)	0
Metabolism and nutrition disorders
Anorexia	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Musculoskeletal and connective tissue disorders
Chills	3/14 (21.4%)	6	1/3 (33.3%)	4	1/7 (14.3%)	1	0/2 (0%)	0	1/2 (50%)	1
Muscle fatigue	1/14 (7.1%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/2 (0%)	0	0/2 (0%)	0
Nervous system disorders
Agitation	2/14 (14.3%)	3	1/3 (33.3%)	1	0/7 (0%)	0	1/2 (50%)	2	0/2 (0%)	0
Forgetfulness	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Headache	11/14 (78.6%)	18	3/3 (100%)	6	5/7 (71.4%)	8	2/2 (100%)	3	1/2 (50%)	1
Restlessness	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Tremor	2/14 (14.3%)	2	0/3 (0%)	0	1/7 (14.3%)	1	1/2 (50%)	1	0/2 (0%)	0
Wired	1/14 (7.1%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/2 (0%)	0	0/2 (0%)	0
Dysequilibrium	2/14 (14.3%)	2	2/3 (66.7%)	2	0/7 (0%)	0	0/2 (0%)	0	0/2 (0%)	0
Paresthesia	1/14 (7.1%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/2 (0%)	0	0/2 (0%)	0
Dizziness	4/14 (28.6%)	4	1/3 (33.3%)	1	2/7 (28.6%)	2	0/2 (0%)	0	1/2 (50%)	1
Psychiatric disorders
Anxiety State	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/2 (50%)	1
Cognitive disturbance	1/14 (7.1%)	2	1/3 (33.3%)	2	0/7 (0%)	0	0/2 (0%)	0	0/2 (0%)	0
Emotional lability	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/2 (50%)	1
Sleep disorder disturbance	6/14 (42.9%)	7	1/3 (33.3%)	1	4/7 (57.1%)	5	0/2 (0%)	0	1/2 (50%)	1
Suicidal ideation	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/2 (50%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/14 (7.1%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Shortness of breath	3/14 (21.4%)	3	2/3 (66.7%)	2	1/7 (14.3%)	1	0/2 (0%)	0	0/2 (0%)	0
Sinus infection	1/14 (7.1%)	2	0/3 (0%)	0	1/7 (14.3%)	2	0/2 (0%)	0	0/2 (0%)	0
Upper respiratory tract infection	4/14 (28.6%)	4	0/3 (0%)	0	4/7 (57.1%)	4	0/2 (0%)	0	0/2 (0%)	0
Vascular disorders
Facial flushing	6/14 (42.9%)	10	1/3 (33.3%)	1	3/7 (42.9%)	7	0/2 (0%)	0	2/2 (100%)	2
Flushing	13/14 (92.9%)	27	3/3 (100%)	6	6/7 (85.7%)	14	2/2 (100%)	5	2/2 (100%)	2
Hot flushes	3/14 (21.4%)	3	1/3 (33.3%)	1	2/7 (28.6%)	2	0/2 (0%)	0	0/2 (0%)	0
Hypotension	2/14 (14.3%)	2	0/3 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	1/2 (50%)	1
Pallor	1/14 (7.1%)	1	0/3 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/2 (0%)	0

Limitations/Caveats

InTiME was based on a novel theory of ME/CFS and an unprecedented drug mechanism. Predicted doses had to be adjusted, limiting statistical inferences, but providing preliminary support for the hypothesis and treatment approach.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.