This clinical trial examines whether Dronabinol, which contains the synthetic psychoactive compound tetrahydrocannabinol (THC), can alleviate severe breathlessness in patients with severe and very severe chronic obstructive pulmonary disease (COPD).

This study is a randomized, controlled, double-blind, crossover trial evaluating the effectiveness of the pharmaceutical drug Dronabinol in patients with severe and very severe COPD.

The researchers will compare the effects of Dronabinol with a placebo (an identical-looking substance that contains no active drug) to determine if Dronabinol reduces breathlessness in COPD patients.

After enrollment, study subjects will undergo four weeks of treatment with both Dronabinol and the placebo in a blinded and randomized sequence. There is a two-week washout period between treatments. During these treatment phases, subjects will complete questionnaires about their daily experiences of breathlessness and wear a watch that records various health parameters.

The study includes eight visits: the initial enrollment and follow-up checks every two weeks. At these visits, subjects undergo tests for lung function and walking distance, and complete health status questionnaires. Additionally, blood samples for THC levels and hair samples for cortisol analysis are collected.

Inclusion Criteria:

• Refractory dyspnea despite optimal treatment
• COPD (GOLD 3,4)
• Breathlessness corresponding to mMRC score ≥ 3
• Informed written consent
• Age ≥ 18 years
• Cognitive relevant, of legal age
• Understands and speaks Danish
• For fertile women defined by amenorrhea for less than 12 months: negative HCG before entry into the trial
• For fertile and sexually active subjects: use of safe contraception during medication intake and 4 weeks after: intrauterine device (IUD) or hormonal contraception (oral contraceptive pill, implant, transdermal patch, vaginal ring or depot injection).

Exclusion Criteria:

• Ongoing infection or exacerbation of COPD within the last month (30 days)
• Regular treatment with THC or CBD within 1 month (30 days)
• Life expectancy less than 3 months (90 days)
• Treatment with medicines that, according to the summary of product characteristics, are strong inhibitors or inducers of CYP3A4, CYP2C9 or CYP2C19
• History of or current evidence of significant medical or psychiatric disorder that is considered by the investigator to put the subject at greater risk of experiencing an adverse event
• Current or past substance abuse where the investigator finds it too risky for the subject to be included in the study

It is the plan to share SAP when this is finalized. It is undecided whether CSR and analytic code will be shared on a platform or available on reasonable request.

An external party will manage the randomization process, assigning participants equally to either the active treatment or placebo groups in a 1:1 ratio. The randomization will be conducted using www.sealedenvelope.com and will incorporate varying block sizes, such as 4, 6, and 8 participants per block. Consequently, each medication container will be labeled with a unique participant number.