Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02370693
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 9
• Location: 1
• Arms: 2
• Duration (Months): 46
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to look at whether bortezomib, mycophenolate or the combination of both is better to treat scarring of the lung caused by Systemic Sclerosis.

Condition or Disease	Intervention/Treatment	Phase
Lung Diseases, Interstitial; Systemic Sclerosis; Scleroderma	Drug: Bortezomib; Drug: Placebo; Drug: Mycophenolate mofetil	Phase 2

Detailed Description

Systemic sclerosis (SSc) is a chronic multisystem autoimmune connective tissue disease for which the etiology remains unknown. The prevalence for SSc is between 19-75 cases per 100,000 and it is more frequent in women, with a peak occurrence in the 4th or 5th decade of life. Morbidity and Mortality in SSc are substantial and pulmonary complications are now the leading cause of death among patients with SSc.

Bortezomib is an FDA approved therapy for the treatment of multiple myeloma and other malignancies. The investigators have data that bortezomib inhibits transforming growth factor (TGF) - signaling in vitro and promotes normal repair and prevents against lung fibrosis in the TGF-mediated intratracheal bleomycin mouse model as well as in a mouse model for skin fibrosis. This is consistent with other data in the literature that proteasomal inhibition can prevent the development of fibrosis. Further there are multiple reports on the efficacy of bortezomib in ameliorating chronic graft-versus-host disease in patients after allogeneic hematopoietic stem cell transplant for multiple myeloma. Bortezomib was also well tolerated in the large clinical trials of multiple myeloma patients with neuropathy and thrombocytopenia the primary adverse events. No pulmonary toxicities were reported in these studies.

Mycophenolate mofetil (CellCept or Myfortic) belongs to a class of medications known as immunosuppressives. This medication was used originally in the management of patients with organ transplants, but is now recommended in the treatment of some autoimmune diseases such as SSc.

Mycophenolate mofetil targets an enzyme in the body called inosine monophosphate dehydrogenase that is important for the formation of deoxyribonucleic acid (DNA) in cells. By interfering with DNA, the medication impairs function of immune system cells that become overactive in autoimmune diseases. Mycophenolate mofetil is currently approved in the treatment of patients with SSc.

This study is being conducted to establish the safety and tolerability of bortezomib in SSc patients at high risk for pulmonary disease progression. In addition, the study will examine the effect of bortezomib on the rate of forced vital capacity (FVC) decline (a physiologic parameter closely associated with disease outcome) and other clinical parameters. In addition the investigators will also measure the effect of bortezomib on biomarkers associated with fibroblast activation. If successful, the study will provide the rationale for a multi-center placebo controlled trial to test the efficacy of bortezomib in SSc patients at high risk for progressive pulmonary disease.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis Grant Number: R34HL122558
• Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Dec 16, 2019
• Actual Study Completion Date: Jan 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: bortezomib plus mycophenolate mofetil Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks	Drug: Bortezomib; Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks; Other Names: Velcade ; Drug: Mycophenolate mofetil; Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks; Other Names: CellCept
Placebo Comparator: Placebo plus mycophenolate mofetil Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks	Drug: Placebo; Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks; Other Names: normal saline ; Drug: Mycophenolate mofetil; Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks; Other Names: CellCept

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Serious Adverse Events [First dosing day to last study visit day: Mean duration 8 months.]

   To assess the safety and tolerability of bortezomib with mycophenolate mofetil assessed by the incidence of serious adverse events.

Secondary Outcome Measures

1. Change of Skin Fibrosis Measured by the Rodnan Skin Score Between Baseline and 24 Weeks [24 weeks]

   The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness that sums individual scores of skin thickness (0 - No Thickening, 1 - Mild Thickening, 2 - Moderate Thickening, 3 - Severe Thickening) measured at 17 body sites to reach a total score (Range: 0 to 51, higher value representing thicker skin). The Score is used as a surrogate for disease activity and severity, and a worsening score over time is associated with worse outcomes.

2. Change of Lung Function Measured by Forced Vital Capacity (FVC) Between Baseline and 24 Weeks [24 weeks]

   Forced vital capacity, or FVC, is the amount in liters of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. It measures the effect that lung disease has on a person's ability to inhale and exhale. Higher values are better, and decreases over time can indicate disease progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Meet established criteria for diffuse or limited systemic sclerosis (SSc) and evidence of pulmonary at high risk of progression with or without progressive skin disease.

• Definition includes subjects who meet the American College of Rheumatology criteria for scleroderma

• High Risk of disease progression (see rationale) will be defined as follows

• If first non-Raynaud's manifestation of SSc < 36 months, then if any of the following are true: FVC <70% predicted or high-resolution computed tomography (HRCT) maximum fibrosis score >3 or FVC < 85% and modified Rodnan skin score (mRSS) increase > 5 over 6 months Regardless of disease duration

• Fall in FVC > 10% over the preceding 12 months or less in the absence of prior therapy or another identified causative process as assessed by the primary scleroderma physician

• Fall in FVC > 10% over 6 months on at least 12 months of prior therapy

• Age > 18 years

• Ability to give informed consent.

• Willingness to discontinue present therapy for the duration of the study

• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

• Male subject agrees to use an acceptable method for contraception for the duration of the study.

• No evidence of acute infection

• Absolute neutrophil count >1000

• Platelets >75,000

• Stable mycophenolate mofetil dose for 16 weeks

Exclusion Criteria:

• Inability to give informed consent or comply with protocol procedures

• FVC < 40% or diffusing capacity of carbon monoxide (DLCO) <30% predicted

• Patient has a platelet count of less than 50,000 within 14 days before enrollment.

• Patient has an absolute neutrophil count of less 1000 within 14 days before enrollment.

• Patient has a calculated or measured creatinine clearance of < 20 ml/minute within 14 days before enrollment.

• Patient has Grade 2 peripheral neuropathy by history within 14 days before enrollment.

• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

• Patient has hypersensitivity to bortezomib, boron or mannitol.

• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum -human chorionic gonadotropin (- hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

• Patient has received other investigational drugs within 4 weeks before enrollment

• Serious medical co-morbidity which in the opinion of the investigator makes participation in the study too high risk

• Psychiatric illness likely to interfere with participation in this clinical study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Manu Jain, MD, MSc, Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 1, 2019

More Information

Publications

None provided.

• Responsible Party: Manu Jain, Professor in Medicine-Pulmonary and Pediatrics, Northwestern University
• ClinicalTrials.gov Identifier: NCT02370693
• Other Study ID Numbers: R34; 1R34HL122558-01A1
• First Posted: Feb 25, 2015
• Last Update Posted: Aug 25, 2021
• Last Verified: Aug 1, 2021

• Keywords provided by Manu Jain, Professor in Medicine-Pulmonary and Pediatrics, Northwestern University: mycophenolate; lung scarring
• Additional relevant MeSH terms: Lung Diseases; Pulmonary Fibrosis; Lung Diseases, Interstitial; Scleroderma, Systemic; Scleroderma, Diffuse; Mycophenolic Acid; Bortezomib

Study Results

Participant Flow

Pre-assignment Detail	2 subjects were enrolled (signed consent form) but did not continue through the screening process far enough to reach randomization.

Arm/Group Title	Bortezomib Plus Mycophenolate Mofetil	Placebo Plus Mycophenolate Mofetil
Arm/Group Description	Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Bortezomib: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks	Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Placebo: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
Period Title: Overall Study
STARTED	3	4
COMPLETED	2	3
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Bortezomib Plus Mycophenolate Mofetil	Placebo Plus Mycophenolate Mofetil	Enrolled But Not Randomized	Total
Arm/Group Description	Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Bortezomib: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks	Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Placebo: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks	Subjects who were enrolled (signed consent form) but did not continue through the screening process far enough to reach randomization.	Total of all reporting groups
Overall Participants	3	4	2	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	4 100%	2 100%	8 88.9%
>=65 years	1 33.3%	0 0%	0 0%	1 11.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.4 (8.1)	52.3 (4.6)	42.6 (10.4)	52.6 (8.9)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	2 50%	0 0%	4 44.4%
Male	1 33.3%	2 50%	2 100%	5 55.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 25%	0 0%	1 11.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	3 100%	3 75%	2 100%	8 88.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	4 100%	2 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Serious Adverse Events
Description	To assess the safety and tolerability of bortezomib with mycophenolate mofetil assessed by the incidence of serious adverse events.
Time Frame	First dosing day to last study visit day: Mean duration 8 months.

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose.

Arm/Group Title	Bortezomib Plus Mycophenolate Mofetil	Placebo Plus Mycophenolate Mofetil
Arm/Group Description	Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Bortezomib: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks	Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Placebo: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
Measure Participants	3	4
Mean (Standard Deviation) [Number of Participants with Serious Adve]	0.33 (.58) 11%	0.25 (.50) 6.3%

2. Secondary Outcome

Title	Change of Skin Fibrosis Measured by the Rodnan Skin Score Between Baseline and 24 Weeks
Description	The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness that sums individual scores of skin thickness (0 - No Thickening, 1 - Mild Thickening, 2 - Moderate Thickening, 3 - Severe Thickening) measured at 17 body sites to reach a total score (Range: 0 to 51, higher value representing thicker skin). The Score is used as a surrogate for disease activity and severity, and a worsening score over time is associated with worse outcomes.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All subjects who had comparable skin score data.

Arm/Group Title	Bortezomib Plus Mycophenolate Mofetil	Placebo Plus Mycophenolate Mofetil
Arm/Group Description	Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Bortezomib: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks	Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Placebo: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
Measure Participants	3	3
Mean (Standard Deviation) [Score on a Scale]	-3.00 (2.65)	-0.33 (0.58)

3. Secondary Outcome

Title	Change of Lung Function Measured by Forced Vital Capacity (FVC) Between Baseline and 24 Weeks
Description	Forced vital capacity, or FVC, is the amount in liters of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. It measures the effect that lung disease has on a person's ability to inhale and exhale. Higher values are better, and decreases over time can indicate disease progression.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All subjects who had comparable forced vital capacity data.

Arm/Group Title	Bortezomib Plus Mycophenolate Mofetil	Placebo Plus Mycophenolate Mofetil
Arm/Group Description	Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Bortezomib: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks	Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Placebo: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
Measure Participants	3	3
Mean (Standard Deviation) [Percentage of change in FVC %predicted]	0.51 (0.55)	-0.69 (1.02)

Adverse Events

Time Frame	First dosing day to last study visit day: Mean duration 8 months.
Adverse Event Reporting Description	Adverse event information collected by study team at each study visit.
Arm/Group Title	Bortezomib Plus Mycophenolate Mofetil		Placebo Plus Mycophenolate Mofetil
Arm/Group Description	Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Bortezomib: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks		Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks Placebo: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
All Cause Mortality
	Bortezomib Plus Mycophenolate Mofetil		Placebo Plus Mycophenolate Mofetil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/4 (0%)
Serious Adverse Events
	Bortezomib Plus Mycophenolate Mofetil		Placebo Plus Mycophenolate Mofetil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		1/4 (25%)
Infections and infestations
Herpes Zoster Infection	1/3 (33.3%)	1	0/4 (0%)	0
Respiratory Syncytial Virus Bilaterial Pneumonia	0/3 (0%)	0	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Bortezomib Plus Mycophenolate Mofetil		Placebo Plus Mycophenolate Mofetil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		4/4 (100%)
Endocrine disorders
Pre-diabetes	0/3 (0%)	0	1/4 (25%)	1
Eye disorders
Dry eyes	0/3 (0%)	0	1/4 (25%)	1
Gastrointestinal disorders
Acid reflux	0/3 (0%)	0	1/4 (25%)	1
Bloating	0/3 (0%)	0	1/4 (25%)	1
Diarrhea	2/3 (66.7%)	5	1/4 (25%)	1
Gastroparesis	1/3 (33.3%)	1	0/4 (0%)	0
Nausea	2/3 (66.7%)	14	0/4 (0%)	0
Upset stomach	1/3 (33.3%)	2	0/4 (0%)	0
Vomiting due to coughing	1/3 (33.3%)	1	0/4 (0%)	0
Worsening diarrhea	1/3 (33.3%)	1	0/4 (0%)	0
General disorders
Ache on forehead and eyelids	0/3 (0%)	0	1/4 (25%)	1
Chills	1/3 (33.3%)	1	0/4 (0%)	0
Cold sweats	1/3 (33.3%)	1	0/4 (0%)	0
Fatigue	2/3 (66.7%)	3	0/4 (0%)	0
Headache	3/3 (100%)	9	1/4 (25%)	2
Shaking	1/3 (33.3%)	1	0/4 (0%)	0
Weight loss of ~10 lbs	1/3 (33.3%)	1	0/4 (0%)	0
Worsened body aches	0/3 (0%)	0	1/4 (25%)	1
Worsened fatigue	0/3 (0%)	0	1/4 (25%)	1
Infections and infestations
Cold	0/3 (0%)	0	1/4 (25%)	1
Injury, poisoning and procedural complications
Bruising at injection site	1/3 (33.3%)	1	0/4 (0%)	0
Burning sensation at injection site	1/3 (33.3%)	2	0/4 (0%)	0
Pain at injection site	1/3 (33.3%)	1	0/4 (0%)	0
Redness at injection site	3/3 (100%)	6	0/4 (0%)	0
Skin peeling at injection site	1/3 (33.3%)	1	0/4 (0%)	0
Tingling at injection site	1/3 (33.3%)	1	0/4 (0%)	0
Soreness at injection site	1/3 (33.3%)	1	0/4 (0%)	0
Warmth at injection site	1/3 (33.3%)	1	0/4 (0%)	0
Metabolism and nutrition disorders
High cholesterol	0/3 (0%)	0	1/4 (25%)	1
Musculoskeletal and connective tissue disorders
Bach ache	0/3 (0%)	0	1/4 (25%)	1
Body aches	0/3 (0%)	0	1/4 (25%)	1
Left ankle pain	0/3 (0%)	0	1/4 (25%)	1
Pain in right shoulder	1/3 (33.3%)	1	0/4 (0%)	0
Right side back muscle spasm	1/3 (33.3%)	1	0/4 (0%)	0
Nervous system disorders
Tingling sensation on face	1/3 (33.3%)	1	0/4 (0%)	0
Renal and urinary disorders
Urinary tract infection	1/3 (33.3%)	1	2/4 (50%)	2
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)	0	1/4 (25%)	1
Cough with increased mucus	0/3 (0%)	0	1/4 (25%)	1
Dry cough	0/3 (0%)	0	1/4 (25%)	2
Dry throat	1/3 (33.3%)	1	0/4 (0%)	0
Nasal congestion	1/3 (33.3%)	1	1/4 (25%)	1
Productive cough	1/3 (33.3%)	1	0/4 (0%)	0
Prolonged coughing episode	1/3 (33.3%)	1	0/4 (0%)	0
Runny nose	1/3 (33.3%)	3	0/4 (0%)	0
Sore throat	1/3 (33.3%)	2	0/4 (0%)	0
Worsened cough	1/3 (33.3%)	3	0/4 (0%)	0
Worsening shortness of breath	0/3 (0%)	0	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Dry Skin	0/3 (0%)	0	1/4 (25%)	1
Surgical and medical procedures
Tooth extraction	1/3 (33.3%)	1	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.