DUAL: Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis Trial

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT02207556
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 32
• Location: 1
• Arm: 1
• Actual Duration (Months): 67.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

In this study the investigators want to find out more about the addition of the antibiotic, doxycycline, to standard anti-amyloid therapy in people with amyloidosis. The investigators want to find out whether doxycycline improves the response to standard anti-amyloid therapy and whether it causes any problems (side effects).

Condition or Disease	Intervention/Treatment	Phase
Primary Systemic Amyloidosis	Drug: Doxycycline	Phase 2

Detailed Description

Organ response to anti-plasma cell therapy in AL amyloidosis tends to lags behind hematologic response as chemotherapy may not clear pre-formed organ amyloid. Doxycycline has been shown to have inhibitory effects on amyloid fibril formation as well as de-fibrillogenic effects and shown to be beneficial in in vitro, murine models and other preclinical studies. The investigators will prospectively evaluate the safety and efficacy of doxycycline in AL amyloidosis patients when used in conjunction with anti-plasma cell chemotherapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis (DUAL) Trial: A Phase II Open Label Study of Oral Doxycycline Administered as an Adjunct to Plasma Cell Directed Therapy in Light Chain (AL) Amyloidosis
• Actual Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: Jul 31, 2017
• Actual Study Completion Date: May 19, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doxycycline Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.	Drug: Doxycycline; Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.; Other Names: Doxycycline monohydrate

Outcome Measures

Primary Outcome Measures

1. Hematologic Response [1 year]

   This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows. Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) < 40 mg/L Partial Response (PR)- dFLC decrease > 50% No Response (NR)- less then PR.

Secondary Outcome Measures

1. Amyloid Organ Response [6 months and 1 year]

   This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney. Heart N-terminal (NT)-proBNP response >30% and > 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression). Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%. Liver ≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound. Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline. Soft Tissue RECIST criteria will be used.

2. Mortality [Baseline, 3 months, 6 months, 1 year]

   The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year

3. Patient-reported Health Quality of Life [Baseline, 3, 6, 9 and 12 months]

   Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.

4. Patient-reported Mental Quality of Life [Baseline, 3, 6, 9 and 12 months]

   Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients with biopsy proven AL amyloidosis.

2. Patients ≥ 18 years of age are eligible.

3. Patient must provide informed consent.

4. All patients must have measurable amyloid organ involvement of a vital organ (eg. heart, liver, kidneys). Localized amyloidosis will also be eligible as long as the amyloid involvement is radiologically measurable.

5. A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted.

6. Patients who have previously been taking doxycycline will be eligible as long as there is no contraindication to stay on doxycycline 100 mg twice daily (BID) for 1 year in the opinion of the treating physician.

7. Creatinine clearance of >25 ml/min.

Exclusion Criteria:

1. Patients with severe malabsorption syndrome precluding absorption of oral agents will be excluded.

2. Known intolerance or allergic reactions with doxycycline.

3. Previous chemotherapy for AL amyloidosis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Froedtert & Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Medical College of Wisconsin
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Anita D'Souza, MD, Medical College of Wisconsin

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 19, 2016
• Informed Consent Form - Sep 14, 2016

More Information

Publications

None provided.

• Responsible Party: Anita D'Souza, Assistant Professor, Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT02207556
• Other Study ID Numbers: 22850; KL2TR001438; K23HL141445; 86-004-26
• First Posted: Aug 4, 2014
• Last Update Posted: Jul 9, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Anita D'Souza, Assistant Professor, Medical College of Wisconsin: AL amyloidosis; amyloidosis; light chain amyloidosis
• Additional relevant MeSH terms: Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Doxycycline

Study Results

Participant Flow

Recruitment Details	Subjects were stratified by the type of amyloidosis. Subjects with primarily organ-based disease were classified as Localized Disease), whereas subjects with hematologic disease were classified as Systematic Disease. Each population received the same intervention but assessment of the clinical outcomes used different classification categories.

Arm/Group Title	Doxycycline (Localized Disease)	Doxacycline (Systemic Disease)
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
Period Title: Overall Study
STARTED	7	25
COMPLETED	5	20
NOT COMPLETED	2	5

Baseline Characteristics

Arm/Group Title	Doxycycline (Localized Disease)	Doxycycline (Systemic Disease)	Total
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.	Total of all reporting groups
Overall Participants	7	25	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 42.9%	16 64%	19 59.4%
>=65 years	4 57.1%	9 36%	13 40.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.3 (10.6)	65.5 (11.4)	62.5 (10.5)
Sex: Female, Male (Count of Participants)
Female	5 71.4%	9 36%	14 43.8%
Male	2 28.6%	16 64%	18 56.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	7 100%	25 100%	32 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	4 16%	4 12.5%
White	7 100%	21 84%	28 87.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	25 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Hematologic Response
Description	This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows. Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) < 40 mg/L Partial Response (PR)- dFLC decrease > 50% No Response (NR)- less then PR.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Hematologic response is not relevant to subjects with localized disease. Subjects with localized disease were not included in this analysis. Five participants had expired by the 1 year time point

Arm/Group Title	Doxycycline (Systemic Disease)
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
Measure Participants	25
Complete Response (CR)	6 85.7%
Partial Response (PR)	3 42.9%
Very Good Partial Response (VGPR)	11 157.1%
Expired at 1 year	5 71.4%

2. Secondary Outcome

Title	Amyloid Organ Response
Description	This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney. Heart N-terminal (NT)-proBNP response >30% and > 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression). Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%. Liver ≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound. Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline. Soft Tissue RECIST criteria will be used.
Time Frame	6 months and 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxycycline (6 Months)	Doxycycline (1 Year)
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
Measure Participants	25	25
Progressive Disease	8 114.3%	3 12%
Stable Disease	8 114.3%	8 32%
Response	6 85.7%	9 36%
Expired	3 42.9%	5 20%

3. Secondary Outcome

Title	Mortality
Description	The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year
Time Frame	Baseline, 3 months, 6 months, 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxycycline (Localized Disease)	Doxacycline (Systemic Disease)
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
Measure Participants	6	25
Baseline	6 85.7%	25 100%
3 Months	6 85.7%	23 92%
6 Months	6 85.7%	22 88%
1 Year	6 85.7%	20 80%

4. Secondary Outcome

Title	Patient-reported Health Quality of Life
Description	Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.
Time Frame	Baseline, 3, 6, 9 and 12 months

Outcome Measure Data

Analysis Population Description

One subject in the Localized cohort withdrew consent prior to the 6-month visit. Five subjects in the Systemic Disease cohort expired during the course of the study; two subjects came off study; and one was lost to follow-up.

Arm/Group Title	Doxycycline (Localized Disease)	Doxacycline (Systemic Disease)
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
Measure Participants	6	25
Baseline	46.1 (9.4)	40.9 (0.3)
3 Months	51.1 (8.8)	40.2 (0.4)
6 Months	48.3 (6.3)	40.6 (0.4)
9 Months	48.9 (8.0)	41.7 (0.5)
12 Months	49.4 (7.7)	44.3 (0.4)

5. Secondary Outcome

Title	Patient-reported Mental Quality of Life
Description	Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.
Time Frame	Baseline, 3, 6, 9 and 12 months

Outcome Measure Data

Analysis Population Description

One subject in the Localized cohort withdrew consent prior to the 6-month visit. Five subjects in the Systemic Disease cohort expired during the course of the study; two subjects came off study; and one was lost to follow-up.

Arm/Group Title	Doxycycline (Localized Disease)	Doxacycline (Systemic Disease)
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
Measure Participants	6	25
Baseline	52.1 (10.4)	47.9 (0.6)
3 Month	51.4 (10.0)	46.0 (0.5)
6 Months	51.2 (9.0)	46.4 (0.5)
9 Months	52.6 (11.9)	46.7 (0.5)
12 Months	50.7 (10.2)	50.6 (0.6)

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Grade was determined using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Events graded as 4 or 5 were considered serious regardless of the standard criteria.
Arm/Group Title	Doxycycline (Localized Disease)		Doxycycline (Systemic Disease)
Arm/Group Description	Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.		Doxycycline will be administered at dose of 100mg orally twice daily for 1 year. Doxycycline: Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
All Cause Mortality
	Doxycycline (Localized Disease)		Doxycycline (Systemic Disease)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		5/25 (20%)
Serious Adverse Events
	Doxycycline (Localized Disease)		Doxycycline (Systemic Disease)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/5 (20%)		13/25 (52%)
Blood and lymphatic system disorders
Lymphocyte production decreased	0/5 (0%)	0	7/25 (28%)	7
Neutrophil Count Decreased	0/5 (0%)	0	6/25 (24%)	6
Platelet Count Decreased	0/5 (0%)	0	10/25 (40%)	10
White Blood Cell Count Decreased	0/5 (0%)	0	5/25 (20%)	5
Death in Hospice	0/5 (0%)	0	1/25 (4%)	1
Thrombosis of Vein of Lower Limb	0/5 (0%)	0	1/25 (4%)	1
Cardiac disorders
Progressive cardiac amyloidosis	0/5 (0%)	0	1/25 (4%)	1
Natural Death	0/5 (0%)	0	1/25 (4%)	1
Gastrointestinal disorders
Colitis	0/5 (0%)	0	1/25 (4%)	1
Hepatobiliary disorders
Aspartate Aminotransferase Increased	0/5 (0%)	0	1/25 (4%)	1
Alanine Aminotransferase Increased	0/5 (0%)	0	1/25 (4%)	1
Infections and infestations
Adenovirus Infection	0/5 (0%)	0	1/25 (4%)	1
Bacterial Sepsis	0/5 (0%)	0	1/25 (4%)	1
Metabolism and nutrition disorders
Hyperuricemia	0/5 (0%)	0	1/25 (4%)	1
Renal and urinary disorders
Chronic Kidney Disease	0/5 (0%)	0	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory Failure	0/5 (0%)	0	1/25 (4%)	1
Skin and subcutaneous tissue disorders
Drug-Induced Lupus	1/5 (20%)	1	0/25 (0%)	0
Other (Not Including Serious) Adverse Events
	Doxycycline (Localized Disease)		Doxycycline (Systemic Disease)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		24/25 (96%)
Blood and lymphatic system disorders
Anemia	0/5 (0%)	0	15/25 (60%)	15
Cardiac disorders
Cardiac Tropinin T Increased	1/5 (20%)	1	4/25 (16%)	4
Tachycardia	0/5 (0%)	0	9/25 (36%)	9
Sinus Tachycardia	0/5 (0%)	0	6/25 (24%)	6
Left Atrium Enlarged	0/5 (0%)	0	4/25 (16%)	4
Palpitations	0/5 (0%)	0	4/25 (16%)	4
Chest Pain - Cardiac	0/5 (0%)	0	3/25 (12%)	3
Irregular Heartbeat	0/5 (0%)	0	3/25 (12%)	3
Right Atrium Enlarged	0/5 (0%)	0	3/25 (12%)	3
Bradycardia	0/5 (0%)	0	2/25 (8%)	2
Chest Tightness	0/5 (0%)	0	2/25 (8%)	2
Murmur, Systolic II/IV	0/5 (0%)	0	2/25 (8%)	2
Sinus Bradycardia	0/5 (0%)	0	2/25 (8%)	2
Ear and labyrinth disorders
Hearing Impaired	1/5 (20%)	1	0/25 (0%)	0
Vertigo	0/5 (0%)	0	2/25 (8%)	2
Eye disorders
Blurred Vison	0/5 (0%)	0	3/25 (12%)	3
Periorbital Edema/Puffiness	0/5 (0%)	0	3/25 (12%)	3
Cataract	0/5 (0%)	0	2/25 (8%)	2
Dry Eye	0/5 (0%)	0	2/25 (8%)	2
Eye Discharge	0/5 (0%)	0	2/25 (8%)	2
Photophobia	0/5 (0%)	0	2/25 (8%)	2
Watering Eyes	0/5 (0%)	0	2/25 (8%)	2
Gastrointestinal disorders
Nausea	2/5 (40%)	2	14/25 (56%)	14
Diarrhea	1/5 (20%)	1	15/25 (60%)	15
Constipation	0/5 (0%)	0	11/25 (44%)	11
Abdominal Pain	0/5 (0%)	0	10/25 (40%)	10
Bloating	0/5 (0%)	0	7/25 (28%)	7
Dry Mouth	0/5 (0%)	0	7/25 (28%)	7
Dysphagia	0/5 (0%)	0	6/25 (24%)	6
Sore Throat	0/5 (0%)	0	6/25 (24%)	6
Vomiting	0/5 (0%)	0	6/25 (24%)	6
Hemorrhoids	0/5 (0%)	0	4/25 (16%)	4
Macroglossia	0/5 (0%)	0	3/25 (12%)	3
Mucocitis, Oral	0/5 (0%)	0	3/25 (12%)	3
Flatulence	0/5 (0%)	0	2/25 (8%)	2
General disorders
Fatigue	3/5 (60%)	3	15/25 (60%)	15
Edema, Limb	2/5 (40%)	2	15/25 (60%)	15
Pain	2/5 (40%)	2	8/25 (32%)	8
Rib Pain	1/5 (20%)	1	0/25 (0%)	0
Fever	0/5 (0%)	0	8/25 (32%)	8
Noncardiac Chest Pain	0/5 (0%)	0	7/25 (28%)	7
Chills	0/5 (0%)	0	5/25 (20%)	5
Gait Disturbance, Unsteady	0/5 (0%)	0	3/25 (12%)	3
Edema, Tongue	0/5 (0%)	0	2/25 (8%)	2
Infections and infestations
Upper Respiratory Infection	2/5 (40%)	2	6/25 (24%)	6
Rhinitis Infective	1/5 (20%)	1	0/25 (0%)	0
Streptococcal Test, Positive	1/5 (20%)	1	0/25 (0%)	0
Upper Respiratory Infection	0/5 (0%)	0	6/25 (24%)	6
Urinary Tract Infection	0/5 (0%)	0	3/25 (12%)	3
Thrush	0/5 (0%)	0	2/25 (8%)	2
Injury, poisoning and procedural complications
Bruising	2/5 (40%)	2	8/25 (32%)	8
Fall	1/5 (20%)	1	9/25 (36%)	9
Sunburn (Burn)	1/5 (20%)	1	0/25 (0%)	0
Inguinal Hernia Repair	0/5 (0%)	0	2/25 (8%)	2
Injury to Lip	0/5 (0%)	0	2/25 (8%)	2
Skin Tear	0/5 (0%)	0	2/25 (8%)	2
Investigations
Hypercalcemia	2/5 (40%)	2	6/25 (24%)	6
Hyperglycemia	2/5 (40%)	2	17/25 (68%)	17
Hyponatremia	2/5 (40%)	2	16/25 (64%)	16
Hyperkalemia	1/5 (20%)	1	7/25 (28%)	7
Hypoalbuminemia	1/5 (20%)	1	15/25 (60%)	15
Hypokalemia	1/5 (20%)	1	14/25 (56%)	14
Weight Gain	1/5 (20%)	1	6/25 (24%)	6
Weight Loss	1/5 (20%)	1	16/25 (64%)	16
Platelet Count Decreased	0/5 (0%)	0	8/25 (32%)	8
Lymphocyte Count Decreased	1/5 (20%)	1	12/25 (48%)	12
White Cell Count Decreased	1/5 (20%)	1	10/25 (40%)	10
Neutrophil Cound Decreased	0/5 (0%)	0	6/25 (24%)	6
AST Increased	1/5 (20%)	1	8/25 (32%)	8
ALT Increased	1/5 (20%)	1	5/25 (20%)	5
Creatinine Increased	0/5 (0%)	0	10/25 (40%)	10
Hypocalcemia	0/5 (0%)	0	10/25 (40%)	10
Alkaline Phosphatase Increased	0/5 (0%)	0	7/25 (28%)	7
Hyopohosphatemia	0/5 (0%)	0	6/25 (24%)	6
Hypomagnesemia	0/5 (0%)	0	5/25 (20%)	5
Bilirubin Increased	0/5 (0%)	0	4/25 (16%)	4
Hypermagnesemia	0/5 (0%)	0	3/25 (12%)	3
Hypernatremia	0/5 (0%)	0	2/25 (8%)	2
Hypoglycemia	0/5 (0%)	0	2/25 (8%)	2
Metabolism and nutrition disorders
Hyperuricemia	2/5 (40%)	2	0/25 (0%)	0
Anorexia	1/5 (20%)	1	11/25 (44%)	11
Low Vitamin D	1/5 (20%)	1	0/25 (0%)	0
Hyperuricemia	0/5 (0%)	0	8/25 (32%)	8
Musculoskeletal and connective tissue disorders
Arthralgia	2/5 (40%)	2	5/25 (20%)	5
Pain in extremity	1/5 (20%)	1	11/25 (44%)	11
Generalized Muscle Weakness	0/5 (0%)	0	10/25 (40%)	10
Back Pain	0/5 (0%)	0	8/25 (32%)	8
Stiffness	0/5 (0%)	0	8/25 (32%)	8
Neck Pain	0/5 (0%)	0	4/25 (16%)	4
Nervous system disorders
Paresthesia	1/5 (20%)	1	6/25 (24%)	6
Dizziness	0/5 (0%)	0	15/25 (60%)	15
Dysgeusia	0/5 (0%)	0	13/25 (52%)	13
Peripheral Sensory Neuropathy	0/5 (0%)	0	8/25 (32%)	8
Headache	0/5 (0%)	0	7/25 (28%)	7
Akathisia	0/5 (0%)	0	2/25 (8%)	2
Hypersomnia	0/5 (0%)	0	2/25 (8%)	2
Psychiatric disorders
Anxiety	1/5 (20%)	1	8/25 (32%)	8
Depression	1/5 (20%)	1	4/25 (16%)	4
Insomnia	0/5 (0%)	0	13/25 (52%)	13
Confusion	0/5 (0%)	0	3/25 (12%)	3
Renal and urinary disorders
Nocturia	1/5 (20%)	1	2/25 (8%)	2
Urine Output Decreased	1/5 (20%)	1	0/25 (0%)	0
Urinary Frequency	0/5 (0%)	0	7/25 (28%)	7
Proteinuria	0/5 (0%)	0	5/25 (20%)	5
Hematuria	0/5 (0%)	0	4/25 (16%)	4
Acute Kidney Injury	0/5 (0%)	0	3/25 (12%)	3
Urinary Incontinence	0/5 (0%)	0	2/25 (8%)	2
Urinary Retention	0/5 (0%)	0	2/25 (8%)	2
Urinary Tract Pain	0/5 (0%)	0	2/25 (8%)	2
Urinary Urgency	0/5 (0%)	0	2/25 (8%)	2
Reproductive system and breast disorders
Night Sweats	0/5 (0%)	0	2/25 (8%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/5 (40%)	2	12/25 (48%)	12
Tachypnea	2/5 (40%)	2	6/25 (24%)	6
Cough	1/5 (20%)	1	12/25 (48%)	12
Laryngeal Hemorrhage	1/5 (20%)	1	0/25 (0%)	0
Lung Crackles	1/5 (20%)	1	0/25 (0%)	0
Hypoxia	0/5 (0%)	0	7/25 (28%)	7
Nasal Congestion	0/5 (0%)	0	7/25 (28%)	7
Epistaxis	0/5 (0%)	0	6/25 (24%)	6
Wheezing	0/5 (0%)	0	4/25 (16%)	4
Hiccups	0/5 (0%)	0	3/25 (12%)	3
Pleural Effusion	0/5 (0%)	0	2/25 (8%)	2
Rales	0/5 (0%)	0	2/25 (8%)	2
Skin and subcutaneous tissue disorders
Bullous Dermatitis	1/5 (20%)	1	0/25 (0%)	0
Contact Dermatitis	1/5 (20%)	1	0/25 (0%)	0
Dry Skin	1/5 (20%)	1	7/25 (28%)	7
Erythema	0/5 (0%)	0	5/25 (20%)	5
Purpura	0/5 (0%)	0	4/25 (16%)	4
Photosensitivity	0/5 (0%)	0	3/25 (12%)	3
Rash	0/5 (0%)	0	3/25 (12%)	3
Erythematous Rash	0/5 (0%)	0	2/25 (8%)	2
Petichial Rash	0/5 (0%)	0	2/25 (8%)	2
Ulceration, Skin	0/5 (0%)	0	2/25 (8%)	2
Vascular disorders
Hypertension	3/5 (60%)	3	6/25 (24%)	6
Hypotension	0/5 (0%)	0	11/25 (44%)	11
Jugular Vein Distention	0/5 (0%)	0	3/25 (12%)	3
Cyanosis	0/5 (0%)	0	2/25 (8%)	2
Flushiing	0/5 (0%)	0	2/25 (8%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.