Evaluation of Paracetamol Withdrawal Versus Continuous Use with Strong Opioids for Pain Management in Patients with Metastatic Cancer Disease

The primary objective of this study is to evaluate whether the **withdrawal** of paracetamol, when used in conjunction with strong opioids, results in inferior pain control compared to the continuous use of paracetamol alongside strong opioids in patients with moderate to severe cancer-related pain. This is clinically relevant as it addresses the potential need for paracetamol in enhancing pain management in patients already receiving strong opioids, which could impact treatment protocols for managing metastatic cancer disease.

Secondary objectives include:

• Assessing whether placebo compared to paracetamol in cancer pain patients already on strong opioids results in more opioid-related side effects.
• Determining if paracetamol withdrawal influences the patient's global impression of change.
• Evaluating whether placebo compared to paracetamol affects patients' opioid consumption.

The clinical trial involves a total of **25 participants** diagnosed with **metastatic cancer disease**, including all incurable solid malignancies in an advanced stage, malignant lymphoma in the palliative setting, and multiple myeloma with bone disease. The study population comprises both male and female subjects aged **18 years and older**, who are under palliative care or oncology service review. Participants are required to have a clinician-predicted life expectancy of more than two months and must be receiving daily regular strong opioids for cancer pain, with a stable scheduled opioid dose for the last 48 hours. Additionally, they must have been taking paracetamol 1 gram three or four times a day for at least five days, with an average pain intensity in the past 24 hours ranging from 2 to 7 on the Numerical Rating Scale (NRS 0-10). The trial population was selected based on these criteria to ensure the study's objectives are met effectively.

The clinical trial is designed as a **randomized**, **double-blind**, parallel-group, non-inferiority phase III withdrawal study. The primary objective is to evaluate whether the withdrawal of **paracetamol** when used in conjunction with strong opioids results in inferior pain control compared to its continuous use in patients with moderate to severe cancer-related pain. The trial will involve participants diagnosed with **metastatic cancer disease**, who are currently receiving regular strong opioids for cancer pain management. The study is expected to run from August 2021 to December 2027, with participant involvement lasting up to 7 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥ 18 years), ability to take oral tablets, and a clinician-predicted life expectancy of more than two months. Eligible participants will be randomized to receive either paracetamol or a **placebo** in addition to their regular opioid regimen. The trial will include follow-up visits to monitor pain intensity and opioid-related side effects, with the primary endpoint being the average pain intensity. Secondary endpoints include patient-reported opioid-related side effects and opioid consumption on Day 8.

The end-of-study visit will occur after the 7-day treatment period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or if their condition deteriorates to a point where continued participation is deemed unsafe. The trial aims to provide valuable insights into the efficacy of paracetamol withdrawal in managing cancer-related pain, potentially influencing future pain management strategies in this patient population.

The clinical trial involves the administration of two treatments: **Paracetamol** and a **Placebo**. The experimental medication, **Paracetamol**, is provided in the form of a tablet, with each tablet containing 1 gram of the active substance. The tablets are manufactured by Karo Pharma AS and are identified by the product code PRD345336. The **Paracetamol** tablets are administered orally, with a maximum daily dose of 4 grams, not exceeding a total of 28 grams over a 7-day treatment period. The marketed product has been modified by milling and compressing into new tablets of 500 mg each. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

The **Placebo** is also administered in tablet form, designed to mimic the appearance and administration route of the **Paracetamol** tablets. The **Placebo** tablets are chemically inert and contain no active pharmaceutical ingredients. They are administered orally, with a maximum daily dose of 4 grams, not exceeding a total of 28 grams over a 7-day treatment period. The use of a **Placebo** in this trial serves as a comparator to evaluate the efficacy of **Paracetamol** in conjunction with strong opioids for managing moderate to severe cancer-related pain. Participant compliance with the **Placebo** dosing schedule is similarly monitored to ensure the integrity of the trial results.

The efficacy of the clinical trial titled "PARASTOP – Paracetamol with Strong Opioids" will be assessed primarily through the evaluation of **average pain intensity**. This primary endpoint will be measured to determine the effectiveness of withdrawing paracetamol in conjunction with strong opioids compared to its continuous use for managing moderate to severe cancer-related pain. Secondary endpoints include patient-reported opioid-related side effects and opioid consumption on Day 8, which encompasses the total amount of scheduled and on-demand opioids used. These efficacy parameters will be collected and analyzed to provide comprehensive insights into the pain management efficacy of the treatment regimens under investigation.