Study Design

From August 2015–May 2017, we conducted a 21-day, single site, two-parallel arm RCT to compare the effects of OLP to treatment as usual (TAU) among cancer survivors reporting at least moderate CRF. In addition, as a retention device and secondary exploratory study, we offered the participants randomized to TAU the opportunity to take OLP for 21 days at the conclusion of the main study, while participants originally randomized to OLP group in main study were offered an opportunity to be followed for an additional 21 days to investigate whether any improvement persists after placebo was discontinued. Participants were compensated up to $75 for their time.

Site, Ethics Statement and Trials Registration

This study was conducted in the University of Alabama at Birmingham (UAB) Comprehensive Cancer Center. The Clinical Trials Review Committee (CTRC) of the Comprehensive Cancer Center and UAB’s Institutional Review Board (IRB) approved this study, and written informed consent was obtained from participants prior to enrollment. The design and procedures of the study were carried out in accordance with the principles of the Declaration of Helsinki. This study was registered with Clinicaltrials.gov on 13/08/15 (NCT02522988).

Study Population

Patients were eligible if they were older than 19 years old, had a cancer diagnosis, had completed cancer treatment between 6 months and 10 years prior to enrollment, and reported at least moderate fatigue (i.e., ≥4 on a 0–10 scale). Clinically significant CRF is defined as ≥3 with categories for CRF as 0 = no fatigue, 1–3 = mild, 4–6 = moderate, 7–10 = severe fatigue18,19. Participants agreed not to change their medications or dosages or to make any major lifestyle changes (i.e., diet or physical activity) during the trial. Participants with uncontrolled medical conditions, such as cardio-vascular disease, hypertension, anemia and diabetes were excluded.

Recruitment and Enrollment

We identified potential participants through medical record examinations and print and media advertisements. Prospective participants identified through medical records received a letter describing the study.

A research specialist screened potential participants, by phone, for eligibility using an a priori script. Potential participants were assessed on a 0–10 scale (i.e., 0 = no fatigue; 10 = as severe as it can be). If the individual’s meet criteria including a fatigue score of ≥4, he or she received more information about the study and, if willing to participate, was scheduled for 2 clinic visits.

Study Measures and Primary Outcomes

Demographic information was collected during the initial screening telephone call (e.g., age, race, gender, cancer type and stage, time since last treatment).

To assess the effects of OLP on CRF, we used two reliable and well-validated questionnaires for CRF: the Fatigue Symptom Inventory (FSI-14) (α = 0.84–0.96) which measures global fatigue symptom severity and the Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF30) (α = 0.84–0.93) which measures the extent to which fatigue disrupts quality of life20,21. The FSI is scored to provide a global score, with lower scores indicative of lower fatigue. MFSI-SF30 produces 5 domain scores: general, physical, emotional, mental health and vigor, as well as a total score. For simplicity and to preserve power, we report only the total score. Lower MFSI-SF30 scores are indicative of lower level of fatigue-disrupted quality of life. Questionnaires were completed at baseline, Day 21, and during the extension exploratory period (i.e., on Days 28 and 49). Patients were asked if there were any placebo-related side-effects at day at Day 11, Day 21 (main study), Day 39 and Day 49 (exploratory period).

Power and Sample Size Calculation

Because there have been no other OLP studies that have investigated the use of an OLP for cancer survivors suffering from CRF, an effect size estimate for our primary outcomes is not known. Therefore, we averaged the effect sizes found in an OLP study of IBS (d = 0.78) and, a feasibility OLP study in major depression (d = 0.54) to determine an estimate of d = 0.6612,16. Assuming a two-group, two-tailed t-test, type 1 error rate of 0.05 and 80% power, we estimated sample size of 40 to detect an effect size of 0.64. For each outcome, our planned sample size calculations indicated that we would have power of 80% assuming a two-tailed two-sample t-test on the outcomes at day 21, Type 1 error rate of 0.05, and we would need a sample size of 80 to detect an effect size of 0.64. Techniques such as ANCOVA or two–sample independent t-test comparing change scores would be powerful or require less sample size to detect the same effect size depending on the correlation between baseline and follow-up measures22. Since the goal of this proof-of-concept study was also to estimate an effect size, our sample size considerations were based on the recommended sample sizes of at least 70 when estimating the pooled standard deviation of the continuous outcome22.

Randomization and Blinding

Before any participant visits, a research specialist, otherwise uninvolved in the study, placed white sheets of paper with 40 “Group 1” (OLP) and 40 “Group 2” (TAU) assignments into 80 opaque envelopes. The envelopes were shuffled and randomly placed in a pre-enrollment allotment of files assigned consecutive numbers. As each qualified participant agreed to enroll in the study, he or she was assigned a consecutively numbered file containing the concealed group assignment. During the first clinic visit, after each participant was consented and received the placebo orientation, (see below) the envelope containing the group assignment was then opened and revealed. Until the envelopes were open at the last moment, the interaction with participants was identical. All assessments were performed by a research assistant blinded to randomized allocation.

Study Procedures: Placebo Orientation and Intervention

Upon arrival for the first clinic visit (Day 1), each participant completed the informed consent process and study questionnaires. Afterwards, all participants met with the Principal Investigator (PI) (TWH), an oncology health behavior specialist, who delivered a rationale with 4 main discussion points, established a priori. The 4 points were: 1) placebo effects are powerful in double-blinded clinical trials and there is some evidence that placebos work even when patients know it’s placebos but we don’t know if they work when honestly prescribed for CRF; (2) placebo responses may be attributed to conditioning, expectancy and biological (e.g., neurological, genetic) factors; 3) an open mind is helpful but unrelated to outcomes that may happen automatically; and, 4) taking the placebo pills as prescribed for 21 days is important (OLP group). The PI delivered these discussion points in a way that fostered emotional support, hope and trust. We also tried to dispel widespread beliefs that placebo effects are negative or unauthentic. Nonetheless, when patients expressed their skepticism about whether placebo pills do anything, which was fairly common, we comfortably acknowledge disbelief is understandable and encouraged them to “see what happens.”

After both groups received the same introduction (which controlled for patient-provider interaction), the PI then opened an opaque envelope revealing the participant’s randomized assignment (i.e., OLP or TAU). If the participant was randomized to OLP, the PI provided pre-packaged pills, clearly labeled “placebos”, along with oral and written instructions to take 2 placebo pills twice per day and how to use the medication diary to track adherence. All participants understood that the placebo pill only contained microcrystalline cellulose and not active ingredients. This was explained during the screening call, during the placebo orientation discussion and when prescribed. Finally, this information was communicated in the written instructions provided to each OLP participant. OLP participants were asked to take 2 placebo pills in the presence of the PI to ensure that there were no swallowing difficulties and advised not to change any other medications. Participants randomized to TAU were asked to continue with their current treatments and were reminded that they could receive the placebo intervention at Day 28 of the study. All participants were contacted by telephone on Day 11 by the PI to inquire about changes in physical condition or medication status and whether participants had additional questions or concerns.

At the main study’s endpoint, the second visit (Day 21), participants met briefly with the research specialist, who was blinded to assignment, and completed the study questionnaires. If participants chose to participate in the extension (exploratory phase) of the study, additional clinic visits were set for the following week (Day 28) and 21 days thereafter (Day 49).

On Day 28, as a reminder, participants who were initially randomized to TAU received identical instructions from the PI as delivered to all participants on Day 1. This meant that this TAU group received the rationale twice. Participants who were randomized to OLP during the main study were scheduled to return for another visit 21 days after the placebos were discontinued. All participants were contacted by telephone on Day 39 by the PI to inquire about changes in physical condition or medication status and to address questions or concerns.

At the final visit of the exploratory study, the blinded research assistant assessed patients (Day 49). Following this, the PI met briefly with the participants to gather anecdotal/qualitative information related to responses to the intervention. (This information will be reported elsewhere.) Finally, a brief educational discussion was held with the participants about additional strategies (i.e., diet, exercise, stress management, sleep hygiene) to manage CRF.

Statistical Analysis

We used a two-sided two sample t-test assuming unequal variances as primary analysis to test differences between the change scores in the OLP and TAU groups on all outcomes. Statistical significance was tested at the 0.05 level. Since both outcomes were pre-specified we did not account for multiple testing. Changes in FSI and MFSI-SF30 scores during the 3-week exploratory follow-up period (day 28 through day 49) among participants were analyzed using a paired sample t-test for both OLP and TAU arms. For each analysis, we calculated Cohen’s d as an estimate of effect size. Given that there was only one drop out (randomized to OLP), missing data was handled using list-wise deletion, which is a valid approach under missing completely at random. Additional sensitivity analyses were done using the non-parametric Wilcoxon rank-sum test. Originally, the study protocol called for an ANCOVA. This analysis was performed for the data used for the main study period and there were no differences found between the ANCOVA and t-test results. For ease of interpretation, we chose to report the t-test results and the ANCOVA outcomes are available upon request.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

CONSORT 2010 Guidelines

This clinical trial conforms to the CONSORT 2010 Guidelines. A completed CONSORT diagram and check list are listed in the manuscript as Fig. 1.

This study is registered withClinicaltrials.gov on 13/08/15 (NCT02522988). https://clinicaltrials.gov/ct2/show/NCT02522988.