SHIVERING 2: Study of High-dose Influenza Vaccine Efficacy by Repeated Dosing IN Gammopathy Patients

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02566265
• Collaborator: (none)
• Enrollment: 122
• Location: 1
• Arms: 2
• Duration (Months): 33
• Patients Per Site Per Month: 3.7

Study Details

Study Description

Brief Summary

The investigators' hypothesis is that the administration of Fluzone® High-Dose with booster to all patients with monoclonal gammopathies (irrespective of age) will lead to seroconversion rates exceeding 50% and more importantly, will reduce influenza-related morbidity, reduce interruptions in cancer therapy and may reduce disease progression at the end of the flu season

Condition or Disease	Intervention/Treatment	Phase
Influenza; Multiple Myeloma; Waldenstrom's Macroglobulinemia; Plasma Cell Disorders; MGUS	Biological: Fluzone High Dose Vaccine; Biological: Standard of care/Placebo	Phase 2

Detailed Description

Influenza is a major cause of morbidity in the US. Patients with monoclonal gammopathies are known to have increased risk of developing influenza. Furthermore, several of the medications (such as proteasome inhibitors), commonly used to treat these tumors, are known to further increase the risk of these tumors. Seasonal influenza vaccination has been shown to reduce influenza related morbidity and is approved for routine prophylaxis in US. In 2009, Fluzone® high- dose vaccine was FDA approved in 2009 for adults aged 65 and older based on the data regarding higher rates of seroprotection (defined as hemagglutination antibody inhibition (HAI) titer of 40 or higher).

In this study, the investigators will administer Fluzone® High-Dose vaccine with a planned booster to patients with monoclonal gammopathies irrespective of age versus a standard of care control group. Primary endpoint is composite of documented influenza infection rate and disease progression (as defined by International Myeloma Working Group criteria) at the end of the flu season. Based on the background data, the investigators expect a higher rate of success in the experimental arm. As such, the investigators power for success rates of 90% and 70% in the experimental and control arms, respectively.

The investigators will also analyze several secondary endpoints including rates of influenza related morbidity, the analysis of humoral and cellular immune response to these vaccines and the rate of disease control (defined as lack of disease progression by standard international myeloma working group criteria).

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Study of High-dose Influenza Vaccine Efficacy by Repeated Dosing IN Gammopathy Patients (SHIVERING 2)
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Oct 1, 2017
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fluzone High Dose Vaccine then Fluzone High Dose Booster Fluzone High dose vaccine administered at Day 0. Fluzone High dose vaccine administered as a booster after 30 days from the initial vaccine.	Biological: Fluzone High Dose Vaccine
Active Comparator: Standard of Care Fluzone High-Dose if age greater than or equal to 65 or Standard dose influenza vaccine if age less than 65 at day 0. Placebo administered 30 days after the initial vaccine.	Biological: Standard of care/Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Failure by Primary Endpoint [1 year]

   Any documented flu infection during the 2015-2016 flu season or evidence of disease progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Understand and voluntarily sign an informed consent form.

• Age ≥18 years at the time of signing the informed consent form.

• Diagnosis of any monoclonal gammopathy: Monoclonal Gammopathy of Undetermined Significance (MGUS), asymptomatic / active multiple myeloma, asymptomatic / active Waldenstrӧm Macroglobulinemia (WM).

Exclusion Criteria:

• Any serious egg allergy or prior serious adverse reaction to an influenza vaccine.

• Use of any other influenza vaccine for the 2015 to 2016 flu season.

• Women who are pregnant or plan to become pregnant in the study period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University	New Haven	Connecticut	United States

Sponsors and Collaborators

• Yale University

Investigators

• Principal Investigator: Andrew Branagan, MD, Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 31, 2017

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT02566265
• Other Study ID Numbers: 1507016111
• First Posted: Oct 2, 2015
• Last Update Posted: Jan 30, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Yale University: influenza; multiple myeloma; Waldenstrom's macroglobulinemia
• Additional relevant MeSH terms: Influenza, Human; Multiple Myeloma; Waldenstrom Macroglobulinemia

Study Results

Participant Flow

Arm/Group Title	Fluzone High Dose Vaccine Then Fluzone High Dose Booster	Standard of Care
Arm/Group Description	Fluzone High dose vaccine administered at Day 0. Fluzone High dose vaccine administered as a booster after 30 days from the initial vaccine. Fluzone High Dose Vaccine	Fluzone High-Dose if age greater than or equal to 65 or Standard dose influenza vaccine if age less than 65 at day 0. Placebo administered 30 days after the initial vaccine. Standard of care/Placebo
Period Title: Overall Study
STARTED	81	41
Day 7 (+/- 2 Days) (Optional)	19	12
Day of Second Vaccine	74	41
30 Days Following 2nd Vaccine	72	35
End of Study Visit (Optional)	38	18
COMPLETED	72	35
NOT COMPLETED	9	6

Baseline Characteristics

Arm/Group Title	Fluzone High Dose Vaccine Then Fluzone High Dose Booster	Standard of Care	Total
Arm/Group Description	Fluzone High dose vaccine administered at Day 0. Fluzone High dose vaccine administered as a booster after 30 days from the initial vaccine. Fluzone High Dose Vaccine	Fluzone High-Dose if age greater than or equal to 65 or Standard dose influenza vaccine if age less than 65 at day 0. Placebo administered 30 days after the initial vaccine. Standard of care/Placebo	Total of all reporting groups
Overall Participants	81	41	122
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	67	66	67
Sex: Female, Male (Count of Participants)
Female	42 51.9%	18 43.9%	60 49.2%
Male	39 48.1%	23 56.1%	62 50.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	81 100%	41 100%	122 100%
Detailed Diagnosis (Count of Participants)
Multiple Myeloma	53 65.4%	28 68.3%	81 66.4%
WM	6 7.4%	4 9.8%	10 8.2%
Other	3 3.7%	1 2.4%	4 3.3%
Asymptomatic Myeloma	8 9.9%	1 2.4%	9 7.4%
Asymptomatic WM	0 0%	3 7.3%	3 2.5%
MGUS	11 13.6%	4 9.8%	15 12.3%
Disease Stage (Count of Participants)
Advanced	64 79%	32 78%	96 78.7%
Early	17 21%	9 22%	26 21.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Failure by Primary Endpoint
Description	Any documented flu infection during the 2015-2016 flu season or evidence of disease progression.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fluzone High Dose Vaccine Then Fluzone High Dose Booster	Standard of Care
Arm/Group Description	Fluzone High dose vaccine administered at Day 0. Fluzone High dose vaccine administered as a booster after 30 days from the initial vaccine. Fluzone High Dose Vaccine	Fluzone High-Dose if age greater than or equal to 65 or Standard dose influenza vaccine if age less than 65 at day 0. Placebo administered 30 days after the initial vaccine. Standard of care/Placebo
Measure Participants	81	41
Count of Participants [Participants]	26 32.1%	13 31.7%

Adverse Events

Time Frame	Adverse event data were collected up to 12 months after initial vaccination
Adverse Event Reporting Description	The definition does not differ.
Arm/Group Title	Fluzone High Dose Vaccine Then Fluzone High Dose Booster		Standard of Care
Arm/Group Description	Fluzone High dose vaccine administered at Day 0. Fluzone High dose vaccine administered as a booster after 30 days from the initial vaccine. Fluzone High Dose Vaccine		Fluzone High-Dose if age greater than or equal to 65 or Standard dose influenza vaccine if age less than 65 at day 0. Placebo administered 30 days after the initial vaccine. Standard of care/Placebo
All Cause Mortality
	Fluzone High Dose Vaccine Then Fluzone High Dose Booster		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/81 (6.2%)		2/41 (4.9%)
Serious Adverse Events
	Fluzone High Dose Vaccine Then Fluzone High Dose Booster		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/81 (9.9%)		1/41 (2.4%)
Gastrointestinal disorders
Small intestinal obstruction	1/81 (1.2%)	1	0/41 (0%)	0
Immune system disorders
Febrile neutropenia	2/81 (2.5%)	2	0/41 (0%)	0
Infections and infestations
Sepsis	0/81 (0%)	0	1/41 (2.4%)	1
Nervous system disorders
Seizure	1/81 (1.2%)	1	0/41 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/81 (1.2%)	1	0/41 (0%)	0
Vascular disorders
Intracranial hemorrhage	2/81 (2.5%)	2	0/41 (0%)	0
Thromboembolic event	2/81 (2.5%)	2	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Fluzone High Dose Vaccine Then Fluzone High Dose Booster		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/81 (0%)		0/41 (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.