Dose-finding Study of Metformin With Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma

• Sponsor: University of Cincinnati (Other)
• Overall Status: Completed
• CT.gov ID: NCT02325401
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Actual Duration (Months): 57.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this research study is to test the safety of adding metformin to standard of care. The standard of care treatment will be cisplatin once every 3 weeks for 3 treatments and radiation for 7 weeks.

Metformin is a medication that is currently used to treat diabetes. Increasing amounts of metformin will be given to groups of patients already receiving normal treatment for their cancer to see if metformin causes any good effects by killing your cancer or bad effects (side effects).

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer	Drug: Metformin; Drug: Cisplatin; Radiation: Radiation Therapy	Phase 1

Detailed Description

Patients were registered by contacting the University of Cincinnati Clinical Trials Office. Patients must be registered and consent obtained prior to initiation of any protocol therapy.

Treatment was administered on an outpatient basis. Adverse events and potential risks for metformin and cisplatin and radiation were reported.

Patients must have screening labs performed within 2 weeks of start of treatment including a complete blood count, liver function tests, metabolic renal panel including magnesium, vitamin B12 level, lactate, and C-peptide. Renal panel must be verified within 24 hours of cisplatin administration. They must fulfill inclusion criteria.

The recommended starting dose of metformin in diabetic patients is 500mg orally twice a day which can be escalated by 500mg increments weekly as tolerated with the maximum recommended daily dose of 2550mg.

Cisplatin was given either before or after the radiation therapy fraction that is given on the same day. If radiation is held for more than 2 days (for any reason), cisplatin may be held as well until radiation resumes.

The prescribed radiotherapy dose was be 70 Gy in 2 Gy once-daily fraction size (total of 35 fractions).

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Dose-finding Study of Metformin in Combination With Concurrent Cisplatin and Radiation in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma
• Actual Study Start Date: May 11, 2015
• Actual Primary Completion Date: Dec 26, 2017
• Actual Study Completion Date: Feb 21, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Metformin with Chemoradiation Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating.

Drug: Metformin; Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation.; Other Names: Fortamet Glucophage Glucophage XR Glumetza Riomet ; Drug: Cisplatin; Dosed at 100mg/m2 on days 1, 22, and 43; Other Names: Platinol Platinol-AQ ; Radiation: Radiation Therapy; 70 Gy in 2 Gy once daily fractions of 35 fractions

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Metformin in Combination With Concurrent Cisplatin and Radiation [24 months]

   Cohorts of patients received escalating doses of metformin (2000 mg, 2550 mg, or 3000 mg divided into daily doses) with a 7-day to 14-day lead-in prior to CRT based on the modified toxicity probability interval design to allow for possible re-escalation after previous de-escalation and to maximize the ability to identify the maximum tolerated dose (MTD). Patients continued to receive metformin for the duration of CRT as tolerated.

Secondary Outcome Measures

1. Number of Participants Experiencing No-Reoccurrence at 36 Months [36 months]

   Patients were evaulated at 36 months to determine if there was recurrence of disease.

2. Number of Participants With Adverse Events [36 months]

   Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.Any participants with any adverse event at any grade was included. Adverse events were collected during the on study period of 21 weeks up to three months after the study for a total of 34 weeks.

3. Progression Free Survival [24 months]

   2-year progression free survival

4. Overall Survival [24 months]

   2 year overall survival

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Locally advanced squamous cell cancer of the head and neck, stage III or IV disease (T1-2, N2a-3 or T3-4).

• Measurable disease

• No prior chemotherapy or radiation for head and neck squamous cell cancer

• Life expectancy of greater than 3 months.

• Adequate labs

Exclusion Criteria:

• Known metastatic disease.

• Nasopharyngeal carcinoma

• History of allergic reactions attributed to metformin or other agents used in study.

• Known diagnosis of diabetes requiring insulin for control.

• Administration of metformin within last 4 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Cincinnati Cancer Institute	Cincinnati	Ohio	United States	45267

Sponsors and Collaborators

• University of Cincinnati

Investigators

• Principal Investigator: Trisha Wise-Draper, MD, University of Cincinnati

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 31, 2017
• Informed Consent Form - Feb 7, 2018

More Information

Publications

None provided.

• Responsible Party: Trisha Wise-Draper, Principal Investigator, University of Cincinnati
• ClinicalTrials.gov Identifier: NCT02325401
• Other Study ID Numbers: UCCI-HN-14-01
• First Posted: Dec 25, 2014
• Last Update Posted: Jun 11, 2020
• Last Verified: May 1, 2020

• Additional relevant MeSH terms: Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Metformin; Cisplatin

Study Results

Participant Flow

Recruitment Details	Patients were 18 years or old, with newly diagnosis LAHNSCC and ECOG rating of better than or equal to 1, with adequate organ function. Individuals were excluded if they had a diagnosis of: nasopharyngeal cancer, metastatic disease, diabetes requiring insulin, or receipt of metformin with in the last 4 weeks, or history of intercurrent illness.

Arm/Group Title	Metformin (2000mg) With Chemoradiation	Metformin (2550mg) With Chemoradiation	Metformin (3000mg) With Chemoradiation
Arm/Group Description	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. This is the 2000mg cohort.	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. This is the 2550mg cohort.	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. This is the 3000mg cohort.
Period Title: Overall Study
STARTED	6	9	5
COMPLETED	6	8	4
NOT COMPLETED	0	1	1

Baseline Characteristics

Arm/Group Title	Metformin With Chemoradiation
Arm/Group Description	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions
Overall Participants	18
Age (Years) [Median (Full Range) ]
Metformin (2000mg) With Chemoradiation	54
Metformin (2550mg) With Chemoradiation	55.5
Metformin (3000mg) With Chemoradiation	53
Sex: Female, Male (Count of Participants)
Female	1 5.6%
Male	5 27.8%
Female	0 0%
Male	8 44.4%
Female	2 11.1%
Male	2 11.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 11.1%
Not Hispanic or Latino	4 22.2%
Unknown or Not Reported	0 0%
Hispanic or Latino	8 44.4%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	0 0%
Hispanic or Latino	0 0%
Not Hispanic or Latino	4 22.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	6 33.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	8 44.4%
More than one race	0 0%
Unknown or Not Reported	0 0%
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 11.1%
White	2 11.1%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%
Tobacco Users (Count of Participants)
Metformin (2000mg) With Chemoradiation	3 16.7%
Metformin (2550mg) With Chemoradiation	7 38.9%
Metformin (3000mg) With Chemoradiation	2 11.1%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Metformin in Combination With Concurrent Cisplatin and Radiation
Description	Cohorts of patients received escalating doses of metformin (2000 mg, 2550 mg, or 3000 mg divided into daily doses) with a 7-day to 14-day lead-in prior to CRT based on the modified toxicity probability interval design to allow for possible re-escalation after previous de-escalation and to maximize the ability to identify the maximum tolerated dose (MTD). Patients continued to receive metformin for the duration of CRT as tolerated.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Proportion of the study sample that were evaulable.

Arm/Group Title	Metformin (2000mg) With Chemoradiation	Metformin (2550mg) With Chemoradiation	Metformin (3000mg) With Chemoradiation
Arm/Group Description	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions
Measure Participants	6	8	4
Number [mg]	NA	NA	NA

2. Secondary Outcome

Title	Number of Participants Experiencing No-Reoccurrence at 36 Months
Description	Patients were evaulated at 36 months to determine if there was recurrence of disease.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin (2000mg) With Chemoradiation	Metformin (2550mg) With Chemoradiation	Metformin (3000mg) With Chemoradiation
Arm/Group Description	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin cohort: 2000mg.	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin cohort: 2550mg.	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin cohort: 3000mg.
Measure Participants	6	8	4
Count of Participants [Participants]	6 33.3%	8 NaN	4 NaN

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.Any participants with any adverse event at any grade was included. Adverse events were collected during the on study period of 21 weeks up to three months after the study for a total of 34 weeks.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin (2000mg) With Chemoradiation	Metformin (2550mg) With Chemoradiation	Metformin (3000mg) With Chemoradiation
Arm/Group Description	Subjects receiving Metformin (2000mg) along with chemoradiation.	Subjects receiving Metformin (2500mg) along with chemoradiation.	Subjects receiving Metformin (2500mg) along with chemoradiation.
Measure Participants	6	8	4
Count of Participants [Participants]	6 33.3%	7 NaN	4 NaN

4. Secondary Outcome

Title	Progression Free Survival
Description	2-year progression free survival
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin (2000mg) With Chemoradiation	Metformin (2550mg) With Chemoradiation	Metformin (3000mg) With Chemoradiation
Arm/Group Description	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions
Measure Participants	6	8	4
Count of Participants [Participants]	6 33.3%	8 NaN	4 NaN

5. Secondary Outcome

Title	Overall Survival
Description	2 year overall survival
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin (2000mg) With Chemoradiation	Metformin (2550mg) With Chemoradiation	Metformin (3000mg) With Chemoradiation
Arm/Group Description	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg, 2550 mg and 3000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions
Measure Participants	6	8	4
Number [participants]	5 27.8%	8 NaN	4 NaN

Adverse Events

Time Frame	Adverse events were collected during the on study period of 21 weeks up to three months after the study for a total of 34 weeks.
Arm/Group Title	Metformin With Chemoradiation- 2000mg Cohort		Metformin With Chemoradiation- 2550mg Cohort		Metformin With Chemoradiation- 3000mg Cohort
Arm/Group Description	Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2000mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions		Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 2550 mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions		Metformin administered orally daily to start one week prior to Cisplatin and Radiation Therapy. Metformin dose is escalating. Metformin: Escalating doses of 3000 mg. Starting 1 week prior to the initiation of chemoradiation and ending the final day of chemo or radiation. Cisplatin: Dosed at 100mg/m2 on days 1, 22, and 43 Radiation Therapy: 70 Gy in 2 Gy once daily fractions of 35 fractions
All Cause Mortality
	Metformin With Chemoradiation- 2000mg Cohort		Metformin With Chemoradiation- 2550mg Cohort		Metformin With Chemoradiation- 3000mg Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		0/8 (0%)		0/4 (0%)
Serious Adverse Events
	Metformin With Chemoradiation- 2000mg Cohort		Metformin With Chemoradiation- 2550mg Cohort		Metformin With Chemoradiation- 3000mg Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		1/8 (12.5%)		1/4 (25%)
Blood and lymphatic system disorders
Febrile Neutropenia	0/6 (0%)	0	1/8 (12.5%)	1	0/4 (0%)	0
Creatinine Increased	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Neutrophil count decreased	1/6 (16.7%)	1	0/8 (0%)	0	1/4 (25%)	1
Cardiac disorders
Atrial fibrillation	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Mucositis Oral	0/6 (0%)	0	1/8 (12.5%)	1	0/4 (0%)	0
Nervous system disorders
Syncope	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	0/6 (0%)	0	1/8 (12.5%)	1	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Lung infection	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Hypoxia	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Metformin With Chemoradiation- 2000mg Cohort		Metformin With Chemoradiation- 2550mg Cohort		Metformin With Chemoradiation- 3000mg Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		7/8 (87.5%)		4/4 (100%)
Blood and lymphatic system disorders
Anemia	3/6 (50%)	4	1/8 (12.5%)	1	1/4 (25%)	1
Lymphocyte count increased	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Thrombotic thrombocytopenic purpura	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Ear and labyrinth disorders
Ear Pain	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Hearing impaired	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Tinnitus	2/6 (33.3%)	2	4/8 (50%)	4	0/4 (0%)	0
Endocrine disorders
Hypothyroidism	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Eye disorders
Photophobia	0/6 (0%)	0	0/8 (0%)	0	1/4 (25%)	1
Gastrointestinal disorders
Abdominal Pain	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Constipation	3/6 (50%)	3	0/8 (0%)	0	1/4 (25%)	2
Diarrhea	1/6 (16.7%)	1	2/8 (25%)	2	3/4 (75%)	4
Dry Mouth	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Dysgeusia	2/6 (33.3%)	2	0/8 (0%)	0	1/4 (25%)	1
Dysphagia	3/6 (50%)	3	0/8 (0%)	0	0/4 (0%)	0
Gastroesophageal reflux disease	2/6 (33.3%)	2	2/8 (25%)	2	0/4 (0%)	0
Mucositis oral	1/6 (16.7%)	1	2/8 (25%)	3	0/4 (0%)	0
Nausea	4/6 (66.7%)	4	4/8 (50%)	4	0/4 (0%)	0
Stomach Pain	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Vomiting	3/6 (50%)	3	2/8 (25%)	2	3/4 (75%)	3
General disorders
Chills	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Edema Trunk	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Fatigue	2/6 (33.3%)	2	1/8 (12.5%)	1	3/4 (75%)	3
Fever	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Pain	0/6 (0%)	0	1/8 (12.5%)	1	0/4 (0%)	0
Hepatobiliary disorders
Alanine aminotransferase increased	2/6 (33.3%)	2	0/8 (0%)	0	0/4 (0%)	0
Alkaline phosphatase increased	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Creatinine increase	1/6 (16.7%)	3	0/8 (0%)	0	2/4 (50%)	2
Infections and infestations
Thrush	2/6 (33.3%)	2	1/8 (12.5%)	1	0/4 (0%)	0
Throat Swelling	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Investigations
Odynophagia	2/6 (33.3%)	2	0/8 (0%)	0	1/4 (25%)	2
Neutrophil count decreased	2/6 (33.3%)	2	0/8 (0%)	0	0/4 (0%)	0
Weight Loss	0/6 (0%)	0	1/8 (12.5%)	1	0/4 (0%)	0
White blood cell decreased	3/6 (50%)	3	1/8 (12.5%)	1	0/4 (0%)	0
Metabolism and nutrition disorders
Hyperglycemia	2/6 (33.3%)	2	2/8 (25%)	3	0/4 (0%)	0
Hyperkalemia	0/6 (0%)	0	0/8 (0%)	0	1/4 (25%)	1
Hypokalemia	0/6 (0%)	0	0/8 (0%)	0	1/4 (25%)	2
Hypomagnesemia	0/6 (0%)	0	0/8 (0%)	0	1/4 (25%)	1
Hyponatremia	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Decreased Appetite	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
VB12 deficiency	0/6 (0%)	0	0/8 (0%)	0	1/4 (25%)	1
Musculoskeletal and connective tissue disorders
Back Pain	1/6 (16.7%)	1	1/8 (12.5%)	1	0/4 (0%)	0
Nervous system disorders
Headache	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Nervous system disorders	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Paresthesia	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Peripheral sensory neuropathy	0/6 (0%)	0	1/8 (12.5%)	1	0/4 (0%)	0
Psychiatric disorders
Depression	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Insomnia	2/6 (33.3%)	2	0/8 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Acute Kidney Disease	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Acute Kidney Injury	4/6 (66.7%)	5	0/8 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	3/6 (50%)	3	0/8 (0%)	0	1/4 (25%)	1
Hiccups	0/6 (0%)	0	0/8 (0%)	0	1/4 (25%)	1
Hoarseness	2/6 (33.3%)	2	0/8 (0%)	0	0/4 (0%)	0
Laryngeal mucositis	0/6 (0%)	0	0/8 (0%)	0	1/4 (25%)	1
Odgnophagia	2/6 (33.3%)	2	0/8 (0%)	0	1/4 (25%)	2
Sore throat	1/6 (16.7%)	1	2/8 (25%)	5	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/6 (16.7%)	1	0/8 (0%)	0	0/4 (0%)	0
Vascular disorders
Hypotension	0/6 (0%)	0	1/8 (12.5%)	1	0/4 (0%)	0
Lymphedema	1/6 (16.7%)	1	0/8 (0%)	0	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.