Clinical trial NCT03771612
Conditions: Inflammation
Keywords: Immune system Social psychology Health psychology
Sponsor: University of California, Los Angeles
Start date: 2022-02-09; Completion date: 2024-06-21
Enrollment: 144 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
UCLA researchers looking for healthy individuals (age 45-60) to participate in a study investigating whether an anti-inflammatory medication can impact daily life experiences.

Everyday for two weeks, participants will take either an anti-inflammatory medication (naproxen) twice daily, or a placebo pill twice daily. Participants will also answer daily questions during the 2-week period. Participants will also fill out questionnaires and complete a few tasks on the computer: once prior to the 2-week period and once immediately after the 2-week period, both during online study sessions.

Detailed description:
Participants (ntotal=50) will be men and women, ages 45-60. All interested participants will first complete a structured telephone interview in order to assess eligibility.

The study will begin with filling out questionnaires, as well as an online session to complete some tasks. You will then be randomly assigned to take either an anti-inflammatory medication (naproxen) or placebo (inactive substance) to take twice daily everyday for the following two weeks. You will also be contacted by text message to remind you to take your pills, to ask if you have taken your pills, and to send you a link to fill out questionnaires once daily. After the two weeks are over, you will again complete questionnaires and the online study session with tasks. Finally, two weeks after the second session, you will receive an email to fill out questionnaires online.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Naproxen intervention 2: Placebos
Intervention descriptions: intervention 1: Half of the participants will be randomly assigned to receive naproxen twice daily (400 mg total daily; 200 mg 2x a day) intervention 2: Half of the participants will be randomly assigned to receive a placebo pill twice daily

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
NCT Study Title: Inflammation and Daily Life Study 
 
Grant Study Title: Can an anti-inflammatory medication reduce loneliness?  
 
NCT: NCT03771612 
 
Original Document Date: January 7, 2022 
 
Modified with Requested Updates: December 20, 2024 
 
 
 


 
 
Study Protocol 
 
Due to the relationships between loneliness and a variety of poor health outcomes and 
mortality, loneliness is increasingly being recognized as an important public health issue. 
Despite the relevance of loneliness for health, including evidence suggesting the effects 
may be particularly pronounced for middle-aged adults, loneliness is a highly 
understudied topic in mid-life in need of further research.  One potential mechanism for 
the effect of loneliness on health is inflammation. Lonely individuals have heightened 
inflammation, and inflammation can increase feelings of loneliness. Furthermore, 
loneliness and inflammation share similar psychological states, both marked by 
hypersensitivity to the social world, including increased sensitivity to both negative and 
positive social cues (i.e., social threat and social reward). Thus, by breaking the cycle 
between inflammation and loneliness, and altering the underlying hypersensitive 
psychological state, it is possible that an anti-inflammatory drug may lead to 
improvements in loneliness. However, to our knowledge, no studies have explicitly 
tested this. The objective of this study is to address this gap in the literature and test the 
effect of an anti-inflammatory medication on loneliness in a sample of middle-aged 
adults and to examine the social psychological mechanisms that may underlie any 
benefits. 
 
This randomized double-blind placebo-controlled study will test the effect of an NSAID 
(naproxen) on loneliness and explore which psychological mechanisms are best 
targeted by an NSAID. Participants, all middle-aged adults screened for high levels of 
loneliness, will be randomized into a 2-week naproxen or placebo intervention. All 
participants will complete pre- and post-intervention sessions online to assess self-report 
psychological outcomes, inflammatory activity, and performance on behavioral tasks.   
 
Participants will be men and women, ages 45-59, who all have high levels of loneliness. 
High loneliness scores will be assessed using the UCLA Loneliness Scale, with eligible 
subjects having a score of 41 or greater (approximately 20-25% of middle-aged adults), 
which has been previously used by our group to define a high loneliness group.  
 
Participants will be recruited from the greater Los Angeles community using 
advertisements. All interested participants will first complete a structured telephone 
interview in order to assess eligibility; prospective participants with co-morbid medical 
conditions or characteristics known to affect inflammation or put them at undue risk will 
be ineligible to participate. Notably, participants with current Major Depressive Disorder 
will be excluded. However, we will control for depressive symptoms in analyses 
examining effects on loneliness to test whether the effect of NSAIDs on loneliness hold 
over and above effects on depression. 
 
At baseline, participants will complete their first session online with an experimenter. 
Here, they will provide blood spots, complete self-report measures as well as several 
psychological tasks. Psychological tasks will include a task in which participants view 
negative social images and make ratings of their affective responses. Participants will 
also include a social/monetary reward task (revised Monetary Incentive Delay Task; 
Knutson et al., 1999) in which they will press a button once a target flashes on the 
screen in order to win money or see a close other or smiling stranger. Reaction times will 
be assessed, with faster reaction times indicating greater reward anticipation. We are 


particularly interested in the difference in reaction times to close others vs. control 
targets. 
 
They will be mailed their pill packs for the intervention. Following the baseline 
assessment, participants will take one 200 mg pill immediately after waking up each day, 
and another 200 mg pill an hour before going to sleep, daily for 2 weeks. By random 
assignment, half of the participants will take naproxen and half will take the same dose 
of placebo. The random allocation sequence will be generated by a statistical consultant 
who was will not be involved in running participants and will be kept by the UCLA 
Pharmacy to ensure proper drug preparation for each participant. Randomization will be 
done using a computerized uniform random number generator; males and females will 
be randomized separately in permuted blocks of 4.  
 
Naproxen was chosen as it is available as a generic (and thus low-cost) drug, has a less 
frequent dosing schedule (i.e., twice daily) than some other NSAIDs (e.g., ibuprofen, 
taken every 4-6 hours), and has been associated with lower risk for adverse 
cardiovascular side effects compared to others NSAIDs. Furthermore, naproxen can 
reduce depressive symptoms in both animals and humans, providing evidence that it 
can affect psychological states. Additionally, the effect of NSAIDs on circulating levels of 
inflammation are inconsistent, but there is some meta-analytic evidence to suggest that 
naproxen specifically may lead to significant decreases in C-reactive protein, suggesting 
naproxen may be one of the best NSAIDs for reducing circulating levels of inflammation. 
The dosing of 400 mg/daily was chosen based on maximum over-the-counter 
recommendations.  
 
Over the 2-week period, subjects will complete daily and weekly (online) measures of 
loneliness, other social psychological outcomes, and any side effects. Additionally, 
participants will receive text message reminders to take their pills, and report on 
symptoms, adherence, and any side effects (monitored by study staff). Participants will 
be asked to report on a full range of symptoms (mild, moderate, severe) in both a 
checklist and an open-ended fashion. Adverse events will be reported to the study 
physician, who will not be blinded to condition. If, at any point in the study, participants 
report mild side effects (e.g., diarrhea, heartburn for 2 consecutive days or more), their 
dose will be reduced by half to 200 mg each day. If participants report moderate to 
severe side effects (e.g., stomach pain, shortness of breath or trouble breathing), they 
will be removed from the study.  At the end of the 2-week intervention, participants will 
get online again with an experimenter to provide another blood sample (to be mailed 
back) as well as to complete self-report measures and behavioral tasks, similar to the 
baseline assessment. In addition, participants will be contacted again 2 weeks later to 
assess measures of loneliness. 
 
IRB amendment (5/2021): 
 
Major changes to study protocol for COVID and financial reasons 
 
 
Minor Amendment - Types of change(s) proposed. 
 
Check all that apply: 
• 
Clarification or technical change 
• 
Minor increase/decrease in number of Study participants 
• 
Narrowing of the inclusion criteria 


• 
Broadening of the exclusion criteria 
• 
Changes in the dosage or form (e.g., tablet to liquid) but not the route of 
administration of an approved drug 
• 
Increase or decrease in the number of safety monitoring visits provided 
that there is no impact on subject safety. 
• 
Addition or deletion of study sites 
• 
Change in payments to study participants 
• 
Minor changes to recruitment materials 
• 
Minor changes to screening procedures 
• 
Change in funding (for example, addition of new funding or completion 
of grant) – Please describe below AND update the funding status in 
section 6.2 in the main application 
• 
Other 
 
 
Major Amendment - Types of change(s) proposed. 
 
Check all that apply: 
• 
Change in study design of a protocol approved by the full board of the IRB 
• 
Change in status of study participants (e.g., study participant becomes prisoner, 
ward, or pregnant in a protocol not approved for these populations (Note: This 
primarily applies to medical or treatment studies.) 
• 
Addition of a procedure not approvable using expedited review procedures (e.g., 
ionizing radiation) 
• 
Changes that increase risk or discomfort to study participants 
• 
Substantive changes to a consent form or other study documents 
distributed to subjects. 
• 
Other 
 
Numerous reasons have converged and required us to change this study protocol 
drastically. First, because of the COVID-19 pandemic, we want to minimize all in-person 
contact as much as possible for participants and staff. Second, the budget/finances 
available to run this study have been drastically reduced because the pandemic as well. 
As such we are proposing the following changes to the study: 
 
• 
Instead of n=100, we will have a final sample of n=50 (necessary for cost-saving) 
• 
As the inflammatory markers were only an exploratory aim of the study, we will 
be eliminating all inflammatory markers / blood draws from the study for cost-
saving reasons, as well as to be able to allow participants to complete the study 
entirely from their own homes for COVID safety reasons. All references to blood 
draws, inflammatory markers, gene expression analyses, medical records, 
medical tests, UCLA health phlebotomy, etc. have been removed from all 
materials/throughout the IRB. 
• 
As such, all study procedures (consent, all questionnaires, tasks, drugs will be 
mailed to participants’ homes, etc.) will take place from the participant’s own 
homes. Participants will complete all questionnaires on their own online via 
Qualtrics. Tasks that would have been done at UCLA with study staff will now be 
done in a virtual session with study staff. All relevant sections/materials of the 
IRB have been updated to reflect this.  


• 
Instead of participants taking naproxen/placebo twice daily for 4 weeks, they will 
take it twice daily for 2 weeks, for both cost-saving and safety reasons.  
• 
As the over the counter indication for naproxen/Aleve is 10 days, and we are 
proposing 14 days, this will also eliminate the need to have any safety blood 
panels completed prior to starting the study. As noted above, all blood draws 
previously done for scientific reasons have been eliminated from this study. As 
such, the safety blood draws are not feasible for this study, for cost reasons. If 
the IRB would be more amenable to 10 days for safety reasons to drop these 
blood draws, we are willing to go down to 10 days as well. 
• 
Relatedly, we have re-classified this study as minimal risk. We have greatly 
reduced the risks associated with this study by cutting down the time of the drug 
in half from 4 weeks to 2 weeks. We are also removing all blood draws 
associated with the study. We believe it is fair to classify this study as minimal 
risk now. 
• 
As the study is considerably safer for participants, with this reduced dosage, and 
that all study procedures will be taking place online, we have changed the 
consent form to be done online by study staff, not just the study physician. 
Participants will be emailed a copy of the consent form to review at their 
convenience. They will be encouraged to ask the study staff any questions they 
have, including the study physician, in advance of signing the consent form. Prior 
to the participant’s signing of the consent form, a member of the study team will 
contact the participant and go over and confirm that the participant has 
understood the form and has no remaining questions. Once they are 
comfortable, participants will sign the consent form virtually by completing a 
Qualtrics form. All relevant sections of the IRB have been updated to reflect this 
change. 
• 
We have shortened the 2-week follow-up online questionnaires to a shorter 
session (30 minutes) and dropped the 4-week survey altogether, for cost-saving 
reasons 
• 
All participant payments and time required has also been updated to reflect the 
shortened study design  
 
IRB amendment (7/2021): 
 
Study amended to include blood spot collection for inflammatory assessment. Blood spot 
collection devices will be mailed to participants and sent back to us for analysis. 
 
 
 
 
 


Statistical Analysis Plan 
 
Primary:  
 
To examine whether naproxen reduces feelings of loneliness, we will use repeated 
measures analyses to examine time (pre- vs. post-intervention) by condition (naproxen 
vs. placebo) interactions on loneliness.  
 
To examine whether naproxen reduces sensitivity to social threat, we will use repeated 
measures analyses to examine time (pre- vs. post-intervention) by condition (naproxen 
vs. placebo) interactions on self-reported ratings to negative social images. We 
anticipate that subjects in the naproxen (vs. control) condition will rate negative images 
as less negative from pre-to-post intervention.  
 
To examine whether naproxen reduces sensitivity to social reward, we will use repeated 
measures analyses to examine time (pre- vs. post-intervention) by condition (naproxen 
vs. placebo) interactions on reaction times to social reward (with faster reactions times 
indicative of greater reward). Specifically, we expect that subjects in the naproxen (vs. 
placebo) condition will show less of a difference in reaction times to viewing close others 
vs. control targets from pre- to post-intervention.  
 
Secondary: 
 
To examine whether naproxen reduces inflammatory gene expression, we will use 
repeated measures to examine time (pre- vs. post-intervention) by condition (naproxen 
vs. placebo) interactions on the inflammatory gene composite measure.  
 
To examine whether naproxen reduces feelings of loneliness at follow-up (2 weeks post-
intervention), we will use repeated measures analyses to examine time (pre- vs. post- 
vs. follow-up intervention) by condition (naproxen vs. placebo) interactions on loneliness.