RAS-HIV: Angiotensin Receptors and Age Related Mitochondrial Decline in HIV Patients

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02606279
• Collaborator: Johns Hopkins University (Other)
• Enrollment: 1
• Location: 1
• Arms: 2
• Duration (Months): 25.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study is designed to evaluate specific factors in mitochondria that may precipitate premature aging and physical weakness in HIV patients. Angiotensin receptors 1 and 2 (AT1R and AT2R) are found in virtually every cell type. This study will evaluate how the relationships among these receptors in immune and skeletal muscle cells change with HIV, and how these changes might trigger mitochondrial dysfunction, declines in muscle strength, and cellular decline in people living with HIV.

Condition or Disease	Intervention/Treatment	Phase
HIV; Aging; Sarcopenia; Angiotensin Receptor Antagonists	Drug: valsartan; Other: Placebo	N/A

Detailed Description

HIV related premature cellular aging and declines in mitochondrial function are closely linked. Dysfunctional mitochondria generate higher levels of reactive oxygen species (ROS) and provide less ATP supply cellular energy. Impaired turnover of damaged mitochondria leads to gradual but progressive decline in energy metabolism, increases in muscle fibrosis and clinically apparent weakness. The Renin Angiotensin System (RAS) is a central hormonal system that contributes to mitochondrial dysfunction and impacts both lifespan and function across multiple organ systems. Deletion of the angiotensin type 1 receptor (AT1R) results in a 25-30% extension of lifespan in mouse models, partly through increasing mitochondrial numbers. Blocking of AT1R reduces a number of age-related morbidities in mice, and in human studies. A plethora of data implicates RAS modulation in marked effects on fitness, frailty and beneficial responses to exercise in older adults. Despite this, there are virtually no data examining RAS biology in HIV+ vs. age-matched HIVsubjects, no data of RAS in relation to key HIV-specific variables (duration of HIV, treatment history, immune markers), and no data examining the effects of blocking AT1R on physical function in HIV infected subjects. In this study, we will examine the RAS and its contribution to premature mitochondrial failure in HIV patients. We will begin to fill this void by enrolling 40 HIV+ subjects in a randomized, double-blinded, placebo controlled pilot study of treatment with AT1R blocker to determine the feasibility of a larger trial, estimate effect size, assess the correlation of angiotensin receptor (AR) expression in peripheral blood cells and muscle cells, and the association of AR expression with physical function measures and immunity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Angiotensin Receptors and Age Related Mitochondrial Decline in HIV Patients
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Aug 4, 2016
• Actual Study Completion Date: Aug 4, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo control 20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm.	Other: Placebo
Experimental: Valsartan 20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm.	Drug: valsartan; Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.; Other Names: Diovan

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in 400m Walk [3, 6, and 9 months post-enrollment]

   Measured by time to finish 400 meter walk

2. Change From Baseline in Grip Strength [3, 6, and 9 months post-enrollment]

   Measured by dynamometer measurement of grip strength

3. Change From Baseline in Quantity of AT1R and AT2R on Monocytes [3, 6, and 9 months post-enrollment]

   Measured by using qPCR and western blot. (Units are arbitrary units)

Secondary Outcome Measures

1. Change From Baseline in Frailty Status [3, 6, and 9 months post-enrollment]

   Evaluated by measurements of grip strength, walking speed and questionnaires

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• able to provide informed consent

• able to attend an extended (~4 hour) Clinical Research Visit

• documented HIV seropositivity

• on a stable anti-retroviral therapy (ART) regimen for at least 12 months

• HIV plasma viral load < 50 copies/ml for at least 6 months

• Systolic blood pressure >110

Exclusion Criteria:

• creatinine > 1.5 ULN (or creatinine clearance < 60 ml/min)

• anti-hypertensive therapy with ACE-I or AT1R-blockers

• inability to perform functional measures (e.g. non-ambulatory without assistance, requires a prosthesis)

• recent (within 30 days) acute illness requiring medical therapy or hospitalization

• immunosuppressive agents (e.g. > 20 mg/d x 2 or more weeks of prednisone or equivalent, chemotherapy) in the last 6 months

• cancer requiring treatment w/in 3 yrs (except for non-melanoma skin cancer)

• blood thinning medications such as Coumadin or Plavix or a bleeding disorder such as hemophilia that could cause complications during muscle biopsies

• pregnancy (will provide urine test for females of child bearing potential)

• regular use of non-steroidal anti-inflammatory drugs or other immune modulating agents.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157

Sponsors and Collaborators

• Wake Forest University Health Sciences
• Johns Hopkins University

Investigators

• Principal Investigator: Katherine R Schafer, MD, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT02606279
• Other Study ID Numbers: WFUHS-28769
• First Posted: Nov 17, 2015
• Last Update Posted: Aug 28, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Sarcopenia; Valsartan

Study Results

Participant Flow

Arm/Group Title	Placebo Control	Valsartan
Arm/Group Description	20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm. Placebo	20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm. valsartan: Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.
Period Title: Overall Study
STARTED	0	1
COMPLETED	0	0
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo Control	Valsartan	Total
Arm/Group Description	20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm. Placebo	20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm. valsartan: Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.	Total of all reporting groups
Overall Participants	0	1	1
Age (Count of Participants)
<=18 years	0 NaN	0 0%
Between 18 and 65 years	1 Infinity	1 100%
>=65 years	0 NaN	0 0%
Sex/Gender, Customized (Count of Participants)
Male	0 NaN	0 0%
Female	0 NaN	0 0%
Prefers not to identify	1 Infinity	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 NaN	0 0%
Not Hispanic or Latino	0 NaN	0 0%
Unknown or Not Reported	1 Infinity	1 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 0%
Asian	0 NaN	0 0%
Native Hawaiian or Other Pacific Islander	0 NaN	0 0%
Black or African American	0 NaN	0 0%
White	0 NaN	0 0%
More than one race	0 NaN	0 0%
Unknown or Not Reported	1 Infinity	1 100%
Region of Enrollment (participants) [Number]
United States	1 Infinity	1 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 400m Walk
Description	Measured by time to finish 400 meter walk
Time Frame	3, 6, and 9 months post-enrollment

Outcome Measure Data

Analysis Population Description

Participant did not complete visits, data not collected.

Arm/Group Title	Placebo Control	Valsartan
Arm/Group Description	20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm. Placebo	20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm. valsartan: Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.
Measure Participants	0	0

2. Primary Outcome

Title	Change From Baseline in Grip Strength
Description	Measured by dynamometer measurement of grip strength
Time Frame	3, 6, and 9 months post-enrollment

Outcome Measure Data

Analysis Population Description

Participant did not complete visits, data not collected.

Arm/Group Title	Placebo Control	Valsartan
Arm/Group Description	20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm. Placebo	20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm. valsartan: Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.
Measure Participants	0	0

3. Primary Outcome

Title	Change From Baseline in Quantity of AT1R and AT2R on Monocytes
Description	Measured by using qPCR and western blot. (Units are arbitrary units)
Time Frame	3, 6, and 9 months post-enrollment

Outcome Measure Data

Analysis Population Description

Participant did not complete visits, data not collected.

Arm/Group Title	Placebo Control	Valsartan
Arm/Group Description	20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm. Placebo	20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm. valsartan: Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.
Measure Participants	0	0

4. Secondary Outcome

Title	Change From Baseline in Frailty Status
Description	Evaluated by measurements of grip strength, walking speed and questionnaires
Time Frame	3, 6, and 9 months post-enrollment

Outcome Measure Data

Analysis Population Description

Participant did not complete visits, data not collected.

Arm/Group Title	Placebo Control	Valsartan
Arm/Group Description	20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm. Placebo	20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm. valsartan: Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.
Measure Participants	0	0

Adverse Events

Arm/Group Title	Placebo Control		Valsartan
Arm/Group Description	20 HIV-infected participants will be randomized into a blinded arm where they will receive 24 weeks of placebo therapy. During this time, they will undergo the same study procedures as the intervention arm. Placebo		20 HIV-infected participants will be randomized into a blinded arm where they receive 24 weeks of valsartan therapy. For those subjects randomized to the valsartan group, they will receive valsartan 40 mg by mouth daily for 2 weeks, then increase to 80 mg by mouth daily for the remaining 22 weeks. During this time, they will undergo the same study procedures as the placebo arm. valsartan: Valsartan will be given in increasing doses (from 40 mg to 80 mg) to those in the valsartan arm.
All Cause Mortality
	Placebo Control		Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/1 (0%)
Serious Adverse Events
	Placebo Control		Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Placebo Control		Valsartan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/1 (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.