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. Author manuscript; available in PMC: 2022 Jul 1.
Published in final edited form as: Pain. 2021 Jul 1;162(7):1899–1905. doi: 10.1097/j.pain.0000000000002188

Table.

Examples of published composite outcomes for pain

Composite outcome Bases for selection of outcome domains or candidate composites Criteria used to select final composite outcome(s)
CLBP (Simon 2007)[19]
Response definition
≥30% improvement in pain AND ≥30% improvement in PGA AND ≤20% worsening in RDMQ

  • Literature review

  • Focus groups with patients

 Step 1: Selected from a development database based on (1) effect size, (2) high χ2 value, and (3) placebo response ≤25%.
Step 2: Ranked using a validation database by χ2 value and number of trials in which the outcome achieved statistical significance. Step 3: Composite candidate chosen because it was identified as the most clinically meaningful based on the included domains and showed <25% responders in the placebo group of all evaluated clinical trials.

  • Analyses were repeated in a second database to investigate consistency.
Neuropathic pain (DPN/PHN) (Patel 2018)[15]
Response definition
≥50% improvement in pain
OR
≥20% improvement in pain AND ≥30% improvement in physical function

  • Literature review

  • Discussions among co-investigators

 Step 1. Selected outcomes that detected a statistically significant treatment effect in 2 datasets of merged pregabalin RCTs.
Step 2. RR of active vs. placebo response were calculated using data from duloxetine and gabapentin studies and examined for consistency.
Step 3. Final selection made based on which consistent outcomes from step 3 correlated best with PGIC.
Knee and Hip OA (Pham, 2003)[16]
Response definition
≥50% improvement in pain
OR
≥50% improvement in pain functionOR
Meets at least 2 of the 3 following criteria:

  • ≥20% improvement in pain AND absolute change of ≥10

  • ≥20% improvement in function AND absolute change of ≥10

  • ≥20% improvement in PGA AND absolute change of ≥10

  • Literature review and presentations, discussions and polling of attendees* of OMERACT 3 conference

  • Subsequent discussions with OMERACT scientific committee.

 Step 1: Calculated the % responders in the active and placebo groups for each candidate composite outcome in 2 separate databases of merged OA RCT data.
Step 2: Noted that the treatment effect sizes (i.e., % responders in the active group - % responders in the placebo group) were similar regardless of the outcome chosen.
Step 3: At the OMERACT 6 conference, workshop participants were asked to vote on which of the outcomes was most appropriate given the fact that they all provided similar effect sizes (79% of participants agreed on the selected outcome).
Fibromyalgia (Arnold, 2012)[1] (2 outcomes)
Response definitions

  1. ≥30% improvement in pain AND ≥10% improvement in physical function

    AND

    30% improvement in fatigue or sleep

  2. ≥30% improvement in pain AND ≥10% improvement in physical function

    AND

    ≥30% improvement in 2 of the following symptoms:
    • Fatigue, sleep, depression, anxiety, cognition

  • Consensus at ACR and EULAR.

  • Association of relevant domains with PGIC in RCTs of drugs that are effective for fibromyalgia.

 Step 1: Selected outcomes with ≥15% response and significant difference between the placebo and active groups in all 12 trials.
Step 2: Selected outcomes with RR of response to active drug vs. placebo with a lower limit of the 95% CI of ≥1.00 in the meta-analysis of trials of all drug types.
Step 3: Identified outcomes with largest RRs and highest percentage responders in the active group.
Efficacy-tolerability composite (ETC) (Katz, 2015)[12]
Percent of study days that the subject was classified as an ETC responder (i.e., ≥20% improvement in pain AND No or mild drug-related AEs)

  • Evaluation of risk-benefit

 Step 1: Identify outcomes that detect a statistically significant difference between a mild and strong opioid (i.e., tapentadol ER and oxycodone CR, respectively).
Step 2: Evaluate the magnitude of the SES between the 3 treatments (i.e., tapentadol, oxycodone, and placebo).
Step 3: Evaluate correlation between the composite ETC score and PGIC and Pain intensity (i.e., original primary outcome of the trial) to evaluate the convergent validity of the outcome.
Rheumatoid arthritis (Felson, 1995)[9]
Response definition
≥20% improvement in tender joint count AND ≥20% improvement in swollen joint count
AND
≥20% improvement in at least 3 of the following:
Pain, PGA, self-assed disability, acute-phase reactant (ESR or CRP)

  • Considered ACR core set of outcomes

  • Proposed outcomes for which 80% of rheumatologists surveyed identified as representing an improvement when asked about real example participant cases from clinical trials.

 Step 1: Identified outcomes with largest effect sizes (treatment vs. placebo).Step 2: Of the outcomes with the largest effect sizes, selected outcomes with the smallest placebo response.

  • Steps 1 and 2 were repeated in data from a separate large clinical trial to assess consistency.

Step 3: Prioritized final candidate outcomes based on which definitions were the easiest to use and which corresponded best with rheumatologists’ impressions of improvement in a follow-up survey.
*

Rheumatologists, epidemiologists, biostatisticians and members of industry and regulatory groups

Abbreviations: Adverse events (AEs); American College of Rheumatology (ACR); chronic low back pain (CLBP); C-reactive protein level (CRP); diabetic peripheral neuropathy (DPN); Efficacy-Tolerability Composite (ETC); Erythrocyte sedimentation rate (ESR); European league against rheumatism (EULAR); Outcome Measures in Rheumatology (OMERACT); Osteoarthritis (OA) Patient Global Assessment (PGA); Patient Global Impression of Chante (PGIC); postherpetic neuralgia (PHN); Randomized clinical trial (RCT); Relative risk (RR); Rolland Morris Disability Questionniare (RMDQ); Standardized effect size (SES).