Venlafaxine in Preventing Chronic Oxaliplatin-Induced Neuropathy In Patients Receiving Combination Chemotherapy

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01611155
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 2
• Actual Duration (Months): 43.2
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

You are being asked to take part in this research study because you are going to be treated with oxaliplatin chemotherapy as part of your standard care. Oxaliplatin commonly causes neuropathy (numbing, tingling and/or pain).The purpose of this study is to compare the effects, good and/or bad, of venlafaxine with a placebo (an inactive agent) on oxaliplatin-induced neuropathy (numbing, tingling and/or pain)

Condition or Disease	Intervention/Treatment	Phase
Peripheral Neuropathy	Drug: venlafaxine; Drug: placebo; Other: questionnaire administration; Other: quality-of-life assessment	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To explore whether venlafaxine can prevent or ameliorate chronic, cumulative neurotoxicity associated with oxaliplatin in cancer patients receiving oxaliplatin, fluorouracil, leucovorin calcium (FOLFOX).

SECONDARY OBJECTIVES:

1. To explore whether venlafaxine can ameliorate acute neuropathy associated with oxaliplatin.

TERTIARY OBJECTIVES:

1. To explore whether venlafaxine can increase the cumulative oxaliplatin doses that can be delivered without dose-limiting chronic neurotoxicity.

2. To explore whether venlafaxine causes adverse events in this setting. III. To explore whether the neuropathy data provided by the Rydel-Seiffer graduated tuning fork is consistent with patient-reported outcome (PRO) measures of chemotherapy-induced peripheral neuropathy (CIPN) and whether this tool might cause different results in patients receiving venlafaxine versus placebo.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive venlafaxine orally (PO) twice daily (BID) beginning on day 1 of and continuing through completion of FOLFOX.

ARM II: Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX.

After completion of study treatment, patients are followed up at 1, 3, 6, 12, and 18 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Pilot Randomized, Placebo-controlled, Double Blind Study of Venlafaxine to Prevent Oxaliplatin-Induced Neuropathy
• Actual Study Start Date: Feb 17, 2012
• Actual Primary Completion Date: Mar 7, 2014
• Actual Study Completion Date: Sep 23, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (management of therapy complications) Patients receive venlafaxine PO BID beginning on day 1 of and continuing through completion of FOLFOX.	Drug: venlafaxine; Given PO; Other Names: Effexor VNF ; Other: questionnaire administration; Ancillary studies; Other: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment
Placebo Comparator: Arm II (placebo) Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX.	Drug: placebo; Given PO; Other Names: PLCB ; Other: questionnaire administration; Ancillary studies; Other: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment

Outcome Measures

Primary Outcome Measures

1. Cycle 1 Sensory Neuropathy Score (Items 31-36, 39, 40 and 48) of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-CIPN20 [Up to 2 weeks]

   The EORTC QLQ-CIPN20 sensory neuropathy score will be calculated using the standard algorithm of EORTC QLQ-CIPN20 and transformed into a 0-100 point scale, where high scores meant less symptom burden. The changes of sensory neuropathy from baseline will be derived by subtracting the baseline score from the sensory neuropathy scores at each cycle of evaluation.

Secondary Outcome Measures

1. Cycle 1 Acute Neuropathy as Measured by EORTC QLQ CIPN20 Motor Subscale (Items 37, 38, 41-45 and 49), and Autonomic Scale (Items 46, 47, 50) [Up to 2 weeks]

   The EORTC QLQ-CIPN20 motor and autonomic neuropathy scores will be calculated using the standard algorithm of EORTC QLQ-CIPN20 and transformed into a 0-100 point scale, where high scores meant less symptom burden. The changes of sensory neuropathy from baseline will be derived by subtracting the baseline score from the sensory neuropathy scores at each cycle of evaluation.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Scheduled to receive FOLFOX chemotherapy with individual oxaliplatin doses of 85 mg/m^2 per cycle given in 2 week cycles (e.g. modified [m] FOLFOX6 or FOLFOX4) Adequate complete blood count (CBC) and creatinine values (per attending physician) obtained =< 28 days prior to registration Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2 Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential Ability to complete questionnaire(s) by themselves or with assistance Life expectancy >= 4 months Strong inhibitors of CYP3A4: > 5-fold increase in the plasma area under the curve (AUC) values or more than 80 % decrease in clearance

• Indinavir (Crixivan®)

• Nelfinavir (Viracept®)

• Atazanavir (Reyataz®)

• Ritonavir (Norvir®)

• Clarithromycin (Biaxin®, Biaxin XL®)

• Itraconazole (Sporanox®)

• Ketoconazole (Nizoral®)

• Nefazodone (Serzone®)

• Saquinavir (Fortovase®, Invirase®)

• Telithromycin (Ketek®) Inducers of CYP3A4

• Efavirenz (Sustiva®)

• Nevirapine (Viramune®)

• Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®)

• Modafinil (Provigil®)

• Phenobarbital (Luminal®)

• Phenytoin (Dilantin®, Phenytek®)

• Pioglitazone (Actos®)

• Rifabutin (Mycobutin®)

• Rifampin (Rifadin®)

• St. John's wort

Exclusion Criteria:

Any of the following:

• Pregnant women

• Nursing women History of an allergic reaction to, or intolerance of, venlafaxine Treatment =< 7 days with other antidepressants, anticonvulsants, monoamine oxidase (MAO) inhibitors, or other neuropathic pain medication agents such as carbamazepine, phenytoin, valproic acid, gabapentin, lamotrigine, topical lidocaine patch or gel, capsaicin cream, or amifostine; in addition, they may not be taking other agents for the treatment of neuropathy, nor other known moderate or strong CYP 2D6 (which consist of Cinacalcet [Sensipar™], quinidine, and Terbinafine [Lamisil®, Lamisil AT®]), nor the strong inducer of CYP 2D6 terbinafine (Lamisil®, Lamisil AT®), nor the following drugs that substantially effect CYP 3A4 Moderate inhibitors of CYP3A4: > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance

• Aprepitant (Emend®)

• Erythromycin (Erythrocin®, E.E.S. ®, Ery-Tab®, Eryc®, EryPed®, PCE®

• Fluconazole (Diflucan®)

• Grapefruit juice

• Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin SR®, Verelan®, Verelan PM®)

• Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®, Cardizem SR®, Cartia XT™, Dilacor XR®, Diltia XT®, Taztia XT™, Tiazac®) Other medical conditions which, in the opinion of the treating physician/allied health professional, would make this protocol unreasonably hazardous for the patient Prior neurotoxic chemotherapy Concurrent radiotherapy Current (within the last month) pre-existing peripheral neuropathy of any grade Uncontrolled hypertension (defined as 3 consecutive readings over the past year of over 160 systolic, and over 100 diastolic)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Principal Investigator: Charles Loprinzi, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01611155
• Other Study ID Numbers: MC11C4; NCI-2012-00318
• First Posted: Jun 4, 2012
• Last Update Posted: Sep 26, 2019
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Peripheral Nervous System Diseases; Venlafaxine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Arm I (Venlafaxine)	Arm II (Placebo)
Arm/Group Description	Patients receive venlafaxine PO BID beginning on day 1 of and continuing through completion of FOLFOX.	Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX.
Period Title: Overall Study
STARTED	25	25
Received Treatment	25	25
COMPLETED	16	18
NOT COMPLETED	9	7

Baseline Characteristics

Arm/Group Title	Arm I (Venlafaxine)	Arm II (Placebo)	Total
Arm/Group Description	Patients receive venlafaxine PO BID beginning on day 1 of and continuing through completion of FOLFOX.	Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX.	Total of all reporting groups
Overall Participants	24	24	48
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.3 (11.3)	58.4 (10.3)	60.3 (10.9)
Sex: Female, Male (Count of Participants)
Female	11 45.8%	12 50%	23 47.9%
Male	13 54.2%	12 50%	25 52.1%

Outcome Measures

1. Primary Outcome

Title	Cycle 1 Sensory Neuropathy Score (Items 31-36, 39, 40 and 48) of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-CIPN20
Description	The EORTC QLQ-CIPN20 sensory neuropathy score will be calculated using the standard algorithm of EORTC QLQ-CIPN20 and transformed into a 0-100 point scale, where high scores meant less symptom burden. The changes of sensory neuropathy from baseline will be derived by subtracting the baseline score from the sensory neuropathy scores at each cycle of evaluation.
Time Frame	Up to 2 weeks

Outcome Measure Data

Analysis Population Description

Patients who completed the (QLQ)-CIPN20 Sensory neuropathy items at cycle 1 are included in this analysis.

Arm/Group Title	Arm I (Venlafaxine)	Arm II (Placebo)
Arm/Group Description	Patients receive venlafaxine PO BID beginning on day 1 of and continuing through completion of FOLFOX.	Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX.
Measure Participants	21	20
Mean (Standard Deviation) [score on a scale]	96.22 (5.88)	95.83 (8.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Venlafaxine), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Cycle 1 Acute Neuropathy as Measured by EORTC QLQ CIPN20 Motor Subscale (Items 37, 38, 41-45 and 49), and Autonomic Scale (Items 46, 47, 50)
Description	The EORTC QLQ-CIPN20 motor and autonomic neuropathy scores will be calculated using the standard algorithm of EORTC QLQ-CIPN20 and transformed into a 0-100 point scale, where high scores meant less symptom burden. The changes of sensory neuropathy from baseline will be derived by subtracting the baseline score from the sensory neuropathy scores at each cycle of evaluation.
Time Frame	Up to 2 weeks

Outcome Measure Data

Analysis Population Description

There were a few Venlafaxine patients who completed the items for the motor subscale but did not complete the items for autonomic subscale in cycle 1 and thus the number analyzed for each subscale is different on the venlafaxine arm.

Arm/Group Title	Arm I (Venlafaxine)	Arm II (Placebo)
Arm/Group Description	Patients receive venlafaxine PO BID beginning on day 1 of and continuing through completion of FOLFOX.	Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX.
Measure Participants	20	21
Motor subscale	97.28 (6.33)	95.98 (6.82)
Autonomic subscale	91.36 (15.03)	90.74 (12.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Venlafaxine), Arm II (Placebo)
	Comments	Motor subscale
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I (Venlafaxine), Arm II (Placebo)
	Comments	autonomic subscale
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Adverse Event Reporting Description	All patients who received treatment and submitted an AE form are included in the summary below.
Arm/Group Title	Arm I (Venlafaxine)		Arm II (Placebo)
Arm/Group Description	Patients receive venlafaxine PO BID beginning on day 1 of and continuing through completion of FOLFOX.		Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX.
All Cause Mortality
	Arm I (Venlafaxine)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/24 (4.2%)		1/25 (4%)
Serious Adverse Events
	Arm I (Venlafaxine)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/24 (8.3%)		2/25 (8%)
Gastrointestinal disorders
Colonic obstruction	0/24 (0%)	0	1/25 (4%)	1
Diarrhea	0/24 (0%)	0	1/25 (4%)	1
General disorders
Edema limbs	0/24 (0%)	0	1/25 (4%)	1
Infections and infestations
Catheter related infection	1/24 (4.2%)	1	0/25 (0%)	0
Metabolism and nutrition disorders
Hypokalemia	0/24 (0%)	0	1/25 (4%)	1
Metabolism and nutrition disorders - Other, specify	0/24 (0%)	0	1/25 (4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/24 (4.2%)	1	1/25 (4%)	1
Vascular disorders
Hematoma	0/24 (0%)	0	1/25 (4%)	1
Thromboembolic event	0/24 (0%)	0	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Arm I (Venlafaxine)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/24 (87.5%)		20/25 (80%)
Blood and lymphatic system disorders
Anemia	1/24 (4.2%)	1	2/25 (8%)	2
Febrile neutropenia	0/24 (0%)	0	2/25 (8%)	2
Gastrointestinal disorders
Lower gastrointestinal hemorrhage	0/24 (0%)	0	1/25 (4%)	1
Mucositis oral	2/24 (8.3%)	2	1/25 (4%)	1
Nausea	15/24 (62.5%)	52	14/25 (56%)	47
Vomiting	0/24 (0%)	0	1/25 (4%)	1
General disorders
Fatigue	1/24 (4.2%)	3	0/25 (0%)	0
Immune system disorders
Allergic reaction	0/24 (0%)	0	1/25 (4%)	1
Anaphylaxis	1/24 (4.2%)	1	0/25 (0%)	0
Infections and infestations
Infections and infestations - Other, specify	1/24 (4.2%)	1	0/25 (0%)	0
Investigations
Blood bilirubin increased	1/24 (4.2%)	1	0/25 (0%)	0
Neutrophil count decreased	6/24 (25%)	19	4/25 (16%)	7
Platelet count decreased	1/24 (4.2%)	7	0/25 (0%)	0
Weight loss	1/24 (4.2%)	1	0/25 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/24 (0%)	0	1/25 (4%)	5
Nervous system disorders
Headache	0/24 (0%)	0	1/25 (4%)	2
Peripheral motor neuropathy	0/24 (0%)	0	1/25 (4%)	2
Peripheral sensory neuropathy	1/24 (4.2%)	1	2/25 (8%)	3
Somnolence	4/24 (16.7%)	4	2/25 (8%)	17
Psychiatric disorders
Agitation	2/24 (8.3%)	2	2/25 (8%)	2
Anxiety	5/24 (20.8%)	19	1/25 (4%)	1
Vascular disorders
Hypertension	7/24 (29.2%)	34	10/25 (40%)	57
Superficial thrombophlebitis	0/24 (0%)	0	1/25 (4%)	1
Thromboembolic event	1/24 (4.2%)	1	0/25 (0%)	0

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.