Placebo effect and its impact on the overall treatment effect

RCTs (randomized, controlled clinical trials) are still the golden standard in clinical research. In RCTs, the most common control group is the Placebo. According to Wikipedia, a placebo is a sham substance or treatment which is designed to have no known therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In order to maintain the blinding (masking), the placebo group may include additional excipients similar to the experimental drug so that the placebo group will have the same characteristics as the experimental drug in shape, size, color, texture, weight, taste, smell,......

Placebo is assumed to have no therapeutic effect or detrimental effect. However, the assumption may not be true especially when the composition of the placebo is in consideration. 

In previous article "Placebo Effect, Honest Placebo, Open-label Placebo", we discussed the placebo effect in diseases in the CNS and psychological area or in diseases with subjective symptom measures. In the post "Placebo effect and the choice of placebo", we discussed the composition of the placebo and some 'placebo' may actually have therapeutic effect. For example, in clinical trials to test the therapeutic effects of IGIV, the  low concentration of albumin may be selected as the placebo control - the low concentration of albumin may actually have the therapeutic effect. In both of these cases, the placebo effect or potential therapeutic effect from the 'placebo' can cause the unexpected higher response rate in Placebo arm, therefore decrease the difference between the experimental drug and the placebo groups, result in the failed trials. 

On the flip side, the placebo can have detrimental effect. There are quite some recent discussions about the placebo having the detrimental effect - consequently, the overall treatment effect observed in the clinical trials may not be due to the therapeutic effect of the experimental drug, but due to the detrimental effect of the placebo group. In other words, the overall treatment effect can be  overestimated due to the detrimental effect of the placebo.

Here are some articles discussing the potential detrimental effects of the placebo in clinical trials to study the effects of fish oil in the prevention of the cardiovascular events. The REDUCT-IT trial was published in NEJM and was the pivotal trial resulting in the FDA and EMA's approval. According to the study protocol, "the matching placebo capsule is filled with light liquid paraffin and contains 0 mg of AMR101 (icosapent ethyl [ethyl-EPA])." The detrimental effect of the placebo may come from the paraffin. 

• Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy
• Amarin stands behind Vascepa after new analysis raises questions about its efficacy
• New analysis of Amarin’s Vascepa resurrects big questions about effectiveness
• New Biomarker Data Add to Concerns Over REDUCE-IT Trial
• Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies

When we conduct the placebo-controlled clinical trials, the composition of the placebo needs to be carefully considered and the potential therapeutic effect from the placebo needs to be minimized. 

Clinical Trial Design: Double-Blind Fixed Duration Trial with Long-term Double-Blind Various Treatment Duration

The randomized, double-blind, parallel-group design is the most common type of design for clinical trials (especially the confirmatory clinical trials). This type of design can be further classified into clinical trials with a fixed treatment duration or with various treatment durations. For clinical trials with a fixed duration, all patients are treated with study drugs for a fixed duration (for example, 16 weeks, 24 weeks, 52 weeks,...) and the primary efficacy endpoint will be estimated at the end of the fixed duration (for example, change from baseline in xxx measure at week 16, week 24, or week 52,...). For clinical trials with various durations such as event-driven study design, patients are treated with study drugs for various durations - the early enrolled patients may receive the study drugs for a much longer time than those later enrolled patients, and patients will stay in the study and receive the study drugs if no protocol-defined event occurs until the required number of events for the study has occurred and the entire study is closed. The event can be Clinical Worsening Event, MACE, Exacerbation, Hospitalization, Progression-free survival, Death,...

In the informed consent form, patients who participate in the clinical trial will be informed how long they may be treated with the experimental drug or placebo. The ethical issue arises if patients are randomly assigned to the placebo group and treated with placebo for a prolonged period of time.     

Lately, we saw several clinical trials with a hybrid approach containing a double-blind fixed duration and then followed by a double-blind various duration. The primary efficacy endpoint was measured at the end of the fixed duration (i.e., week 52 for INBUILD and ISABELLA trials and week 24 for STELLAR trial). The double-blind various duration was added to the trial to collect the information for secondary and exploratory endpoints that need a longer exposure time. The double-blind various duration depends on the enrollment speed and the timing of patients entering into the study. Early-enrolled patients will stay in the study much longer than the later-enrolled patients. The slower the enrollment speed is, the longer the double-blind various duration takes. 

INBUILD study: Nintedanib in Progressive Fibrosing Interstitial Lung Diseases 

For each patient, the trial consisted of two parts: Part A, which was conducted during the first 52 weeks, and Part B, which was a variable treatment period beyond week 52 during which patients continued to receive either nintedanib or placebo until all the patients had completed Part A. 

The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based on efficacy and safety data over 52 weeks.

The primary analysis of this study will therefore be performed once the last randomized patient reaches the Week 52 Visit (Visit 9 at the end of Part A). At that time, a database lock will occur and all the data will be unblinded. Efficacy and safety analyses will be performed on the data from Part A of the trial to assess the benefit-risk of nintedanib over 52 weeks. In addition, data collected in Part B of the trial (after 52 weeks) and available at the time of data cut-off for the primary analysis will be reported together with data from Part A (i.e. over the whole trial).

Once the benefit-risk assessment of nintedanib over 52 weeks is confirmed to be positive, all patients receiving trial medication in Part B will be offered open-label treatment with nintedanib in a separate study.

Trial 1199.247 i.e. Part B will continue until all patients have been switched to open-label nintedanib or completed the Follow-up Visit. A final database lock will then occur and Part B data collected between the data cut off for the primary analysis and the final database lock will be reported together with data from Part A i.e. over the whole trial.

ISABELLA Studies: GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis

See the paper: Rationale, design and objectives of two phase III, randomised, placebo controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2)

In each study, approximately 750 subjects will be randomized 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or matching placebo, once daily, in addition to local SOC. SOC is defined as either pirfenidone or nintedanib, or neither pirfenidone nor nintedanib (for any reason). Treatment will continue for at least 52 weeks (subjects will continue to receive randomized treatment until the last patient reaches 52 weeks in the study). A follow-up visit will be conducted 4 weeks after the end-of-study visit (figure 1 below).

STELLAR Study: Sotatercept in Pulmonary Arterial Hypertension

According to Acceleron's ATS 2021 INTERNATIONAL CONFERENCE ACCELERON INVESTOR AND ANALYST CALL, the STELLAR study was designed as the following:

The double-blind fixed duration is 24 weeks and the primary efficacy endpoint (6MWD) is measured at week 24. The double-blind various duration had a cap at 72 weeks, i.e., the maximum duration for the period is 72 weeks). Patients can be in the long-term double-blind treatment period for 0 (the last enrolled patient) to 72 weeks (early enrolled patients). 

Placebo and Sham treatment: are they really inactive?

According the ICH guidance E10 (CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL TRIALS), "A placebo is a "dummy" treatment that appears as identical as possible to the test treatment with respect to physical characteristics such as color, weight, taste and smell, but that does not contain the test drug."

We typically use the term Placebo, but sometime, the term 'sham treatment' is used. The word 'sham' means something that is a fake or an imitation that purports to be genuine.

In practice, a placebo is often defined as an inactive substance made to appear like a medication or a sham procedure or device imitating a known treatment. Sometimes, the 'inactive' substance used in the clinical trial may not be totally 'inactive'. One example is albumin. On the one hand, the albumin may be treated as inactive substance for Placebo; on the other hand, there are studies to study the effect of albumin in certain diseases. In a study about "the Effectiveness of Intravenous Immune Globulin (10%) for the Treatment of Multifocal Motor Neuropathy", 0.25% human albumin solution was used as Placebo. But there are also plenty of clinical trials to study the efficacy of albumin in sepsis, renal impairment, acute stroke,...

In a lot of publications, the author did not disclose what the placebo is. You can use the same term 'placebo', but the 'placebo' could be sugar pill, saline, albumin,...

Even more...

In article web article by BJ Appelgren titled "The Placebo as Medicine Viewed as Sham, Placebo Itself May Be the Most Significant", the following examples are cited as other type of placebos.

• Having an interaction with a health care provider
• The presence of something symbolic in the encounter such as contact with a person wearing a “white coat,” perceived as a provider of healing

The significance of symbols cannot be measured objectively and, for that reason, is not valued. Researchers also have an additional puzzle when non-treatment causes positive results. Too often, when the effect of symbolism is recognized by conventional medicine, it is removed from a context of positive meaning and denigrated as “being all in the mind,” as if that makes it illusory.