Efficacy of Non-opioid Drugs in Addition to Opioid Therapy for Cancer Pain Management (NoDoubt)

Experimental: Opioid + Metamizole

Arzneimittel: Metamizole

Metamizole 4 g/d as: 2 capsules of 500 mg Metamizole each (1000 mg) taken 4 x daily orally.

Experimental: Opioid + Ibuprofen

Arzneimittel: Ibuprofen

Ibuprofen 1.2 g/d as: 2 capsules of 150 mg Ibuprofen each (300 mg) taken 4 x daily orally

Placebo-Komparator: Opioid + Placebo

Sonstiges: Placebo

Placebo 0 g/d as: 2 capsules containing inactive substance (mannitol) taken 4 x daily orally.

Change in cancer pain

The primary outcome will help to determine whether adding metamizole (dipyrone) or ibuprofen to opioids is more effective than adding placebo in reducing average daily pain intensity (primary outcome) in cancer patients.

- Average of 5-day average daily patient reported pain assessed on days 3 to 7 by numeric rating scale (NRS); The NRS ranges from 0 ("no pain") to 10 ("pain as bad as the patient can imagine")

Assessment of equivalence of metamizole and ibuprofen in analgesic potency regarding the pain intensity

Our main secondary outcome will help to investigate whether metamizole and ibuprofen demonstrate similar analgesic potency (are equivalent) regarding the pain intensity. For assessment of equivalence, Average of 5-day average daily patient reported pain assessed on days 3 to 7 by numeric rating scale will be used.

Time to pain control [in days]

1. Time until minimal clinically important difference (MCID) of 1 is achieved
2. Time until PSG is achieved

MCID and PSG achieved (Yes/No) will be assessed daily from day 3 to 7.

≥30% reduction in daily average pain (Yes/No)

This outcome will be assessed based on the average of daily patient reported pain intensity by NRS at baseline (BL-pain) compared to the daily average pain on the last day of the intervention period (day 7).

Burden through interference of pain with general activity by NRS

Will be assessed at baseline and daily from day 3 to 7 using item 9 A ("General activity") of the BPI-SF. The NRS ranges from 0 ("does not interfere") to 10 ("completely interferes"). Both outcomes will also be assessed at EOS.

Burden through interference of pain with mood by NRS

Will be assessed at baseline and daily from day 3 to 7 using item 9 B ("Mood") of the BPI-SF. The NRS ranges from 0 ("does not interfere") to 10 ("completely interferes"). Both outcomes will also be assessed at EOS.

Number of opioid rescue medications per day

The daily number of IROs (Immediate Release Opioids) will be assessed.

Number of pain episodes

This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS.

Duration [in minutes] of pain episodes

This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS.

Worst pain in the past 24 hours by NRS

This outcome will be assessed at baseline and daily from day 3 to 7 using item 3 of the BPI-SF (Brief Pain Inventory - Short Form). The NRS ranges from 0 ("no pain") to 10 ("pain as bad as the patient can imagine"). It will also be assessed at End of Study Visit (EOS).

Least pain in the past 24 hours by NRS

This outcome will be assessed at baseline and daily from day 3 to 7 using item 4 of the BPI-SF. The NRS ranges from 0 ("no pain") to 10 ("pain as bad as the patient can imagine"). It will also be assessed at EOS.

Daily differences in pain intensity measured by NRS

This outcome will be assessed daily from day 3 to day 7 to investigate efficacy over the course of time. The NRS ranges from 0 ("no pain") to 10 ("pain as bad as the patient can imagine")

Patient's Individual Primary Goal (IPG) achieved

The IPG will be specified at baseline and whether it has been achieved or not will be assessed at EOS based on the specified IPG at baseline.

The IPG reflects variation between individuals' analgesic goals and further individualize symptom assessment by allowing each patient to specify a primary goal regarding the amelioration of the main issue as asked at baseline (i.e., patient's most important item from this list: average pain, pain interference with mood or activity, number or duration of pain episodes, worst pain, other).

Personal Symptom Goal (PSG) achieved

The PSG will be specified at baseline (NRS 0-10) and whether it has been achieved or not will be assessed daily from day 3 to 7.

Patients are asked at baseline "At what level would you feel comfortable with this symptom?" to identify the maximal symptom intensity they would consider comfortable on the NRS ranging from 0 ("no pain") to 10 ("pain as bad as the patient can imagine").

Patient Global Impression of Pain Change (PGIC) by verbal rating scale (VRS)

A 7-option rating-of-change scale to assess participant-reported response to pain therapy using a VRS ("very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse").

Morphine Equivalent Daily Dose (MEDD) (in mg) calculated by compound, dose and application route of IROs (Immediate Release Opioid) and EROs (Extended-release Opioids)

Baseline MEDD and MEDD at EOS will be assessed. This outcome will be assessed daily between day 1 and 7.

MEDD is calculated by multiplying the daily dose of the prescribed opioid (if not already morphine) by a compound-specific, route of application-dependent conversion factor.

The opioid conversion ratios used to calculate MEDD are based on the literature and practical clinical considerations on equianalgesic dosing.

Number of patients with ≥30% reduction in pain

For this outcome, the number of patients achieving ≥30% reduction in pain will be assessed, comparing pain at baseline (BL-pain) to the daily average pain on the last day of the intervention (day 7)

Adherence to protocol and IMP intake

Discharge during d1-d7 will be assessed (Yes/No), including time to discharge after inclusion, if applicable.

IMP intake (i.e., missed doses day d1-d7) will be assessed daily.

Number of participants that opened the capsules

Administration assessed daily as "Capsules opened: Yes/No".

Number of participants that received the IMP through an enteral tube

Assessed daily as "Administration through enteral tube": Yes/No, if "capsules opened: Yes"

Continuation of non-opioid treatment

This will be assessed at EOS based on the clinical decision at physician's discretion (after unblinding). It will be assessed whether the non-opioid is continued, discontinued, switched, or if a (new) non-opioid is initiated. If applicable, the drug and the daily dose (mg/24 h) will be assessed.

Differences in treatment response based on CRP (C-reactive protein) status at baseline

The CRP measured at baseline will be used to exploratively assess whether treatment response differs according to baseline inflammatory status as measured by CRP (i.e., whether baseline inflammation may act as a potential effect modifier of the observed treatment response).

Changes in symptoms at EOS compared to baseline

Using ESAS (Edmonton Symptom Assessment System):

This scale is designed to help assess pain, tiredness, drowsiness, nausea, depression, anxiety, appetite, wellbeing, and shortness of breath. The blank scale can be used to assess "other problems" as needed. Each symptom's severity at the time of assessment is rated from 0 to 10; 0 meaning the symptom is absent and 10 being the worst possible severity.

Changes in activity levels at EOS compared to baseline

Average activity levels of the past 7 days will be assessed at baseline and at EOS using a NRS (numeric rating scale) ranging from 0 (no activity at all) to 10 (maximum possible activity/the same as in health).

Accuracy of participant treatment guess

(Correct vs incorrect vs unsure) based on comparison with actual treatment allocation

Incidence of (serious) adverse events ((S)AEs)

Type and duration of (S)AEs

Number of dropouts due to decrease in creatinine-estimated (e)GFR <30 ml/min and/or ≥1.5-fold increase in baseline serum creatinine attributed to ibuprofen

Number of dropouts due to clinically relevant decrease in leukocyte count (≥50% from baseline) attributed to metamizole

Changes in performance status (ECOG) at EOS compared to baseline

Using the ECOG (Eastern Cooperative Oncology Group) performance status. It describes a patient's level of functioning based on the ability to perform self-care, daily activities, and physical activities (e.g., walking and working). The scale runs from 0 to 5, where lower numbers indicate better functioning. However, as 5 indicates death, only 0 to 4 are used for assessment of this outcome.