Mycotoxin potential contamination of one lot of study drug

Cancer causes pain in many of the patients that it affects. Physicians specialized in palliative care help advanced cancer patients to maintain as good pain control as possible through the use of medications such as opioids. Even with palliative care and optimal use of medications, many patients still suffer enormously as the cancer spreads. Because of this, some cancer patients also try or use cannabis in different ways to relieve their pain and improve the way they feel. However, there has not been much high-quality research done yet to prove whether or not cannabis products are truly useful to relieve severe cancer pain. This study is to test if advanced cancer patients who use inhaled medical cannabis (PPP001), in addition to palliative care management, will experience improvement in quality of life and relieve uncontrolled pain, providing safety conditions.

This is a 4-week randomized, double-blind, placebo-controlled, parallel group design trial to evaluate the safety and efficacy of inhaled PPP001 to improve quality of life (HRQoL) and reduce pain intensity, in patients with uncontrolled cancer pain and incurable malignancy.

Nine hundred forty six adult patients, male and female, with chronic cancer pain (at least 3 months in duration) and advanced disease, with an average weekly pain intensity score greater than 4 on a 11 points Numerical Rate Scale (NRS), will be prospectively recruited and invited to participate in this trial.

Informed consent will be obtained by a Research Assistant.

After baseline documentation with standardized scales, patients will be randomized to one of 2 parallel groups:

Group A: 4 weeks PPP001-kit three times daily; Group B: 4 weeks placebo-kit three times daily; The inhalation of PPP001 or placebo-kit will be allowed three times a day at 4-6 hour intervals. Rescue medication will also be allowed.

Patients will have a dose titration phase during the first week, followed by an additional 3-week period of treatment. The dose escalation will allow patients to adapt to the potential AEs of cannabis.

Patients will have follow-up after 1 week and 4 weeks of treatment. Once the patient has completed 4 weeks of inhaled PPP001 or placebo, it will be rolled into a long-term follow-up phase until drop-out or death. All patients, including the ones in the placebo group, will be allowed to receive the active treatment once the 4-weeks trial has finished, and continue it until death or drop-out.

Inclusion Criteria:

1. Written informed consent

2. Adult male and female patients at least 18 years of age

3. Subject agreed to follow the protocol

4. Advanced cancer for which there is no known curative therapy

5. Patients experiencing pain ≥4 on NRS due to cancer related pain

6. Life expectancy six weeks or longer

7. PPI score less than or equal to 4 (survival more than 6 weeks)

8. PPS greater than or equal 70%

9. PaP Score Group A (30-day survival probability >70%)

10. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

11. The patient has a clinical diagnosis of cancer related pain, which is not alleviated with their current optimized opioid treatment

12. The patient is using no more than one type of breakthrough opioid analgesia

13. Normal cognitive status according to MDAS and MiniCog

14. Normal liver function (defined as aspartate aminotransferase 10-40 U/L and alanine aminotransferase 7-56 U/L)

15. Normal renal function (defined as serum creatinine level <133 µmol/L and Estimated Glomerular Filtration Rate (eGFR) greater than or equal to 60)

16. The patient is able to perform deep inhalations and hold breath for at least 5 to 10 seconds. If there is any pulmonary disease diagnosed previously (obstructive and/or restrictive pathology), the patient must be able to perform a maximal inhalation of at least 12-15 ml/kg measured with an incentive spirometer, followed by a normal exhalation

17. Ability to read and respond to questions in French or English.

18. Previous or current use of opioid analgesics (at least 1 week)

19. A female volunteer must meet one of the following criteria:

    If of childbearing potential - agrees to use one of the accepted contraceptive regimens from at least 28 days prior to the first drug administration, during the study and for at least 60 days after the last dose. An acceptable method of contraception includes one of the following:

    • Abstinence from heterosexual intercourse
    • Systemic contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
    • Intrauterine device (with or without hormones)
    • Condom with spermicide or condom with intravaginally applied spermicide If of non-childbearing potential - should be surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least one year without menses)

20. A male volunteer with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must meet the following criteria:

    • Participant is unable to procreate, defined as surgically sterile (i.e. has undergone a vasectomy within the last 6 months)
    • Participant agrees to use one of the accepted contraceptive regimens from first drug administration until 3 months after the last drug administration. An acceptable method of contraception includes one of the following:

A. Abstinence from heterosexual intercourse. B. Condom with spermicide or condom with intravaginally applied spermicide

Exclusion Criteria:

1. Pain due to other causes different than cancer related pain
2. Previous serious adverse event or hypersensitivity to cannabis or cannabinoids
3. Inability to understand and comply with the instructions of the study
4. Presence of significant cardiac disease (history of unstable ischemic heart disease, heart failure, severe and uncontrolled hypertension) that, in the opinion of the investigator, would put the patient at risk of a clinically significant arrhythmia or myocardial infarction
5. Current substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM 5)
6. Life-time history of dependence on cannabis or diagnosis of cannabis use disorder (CUD) according to the DSM 5
7. Life-time history of DSM 5 schizophrenia, bipolar disorder, or previous psychosis with or intolerance to cannabinoids
8. Current or history of suicidal ideation according to the Columbia-Suicide Severity Rating Scale (C-SSRS) approved by FDA in 2012 for assessment of suicidal ideation and behaviour
9. Pregnant, breast-feeding or female patients of child-bearing potential and male patients whose partner is of child-bearing potential, unless willing to ensure that they or their partner use effective contraception, for example, oral contraception, double barrier, intra-uterine device, during the study and for three months thereafter (however, a male condom should not be used in conjunction with a female condom as this may not prove effective)
10. Hepatic impairment (aspartate aminotransferase more than three times normal) or renal function impairment (serum creatinine level >133 µmol/L, Estimated Glomerular Filtration Rate (eGFR) <60)
11. Cognitive impairment according to MDAS and MiniCog
12. Patient has any planned clinical interventions that would affect their pain (e.g., chemotherapy or radiation therapy where, in the clinical judgment of the investigator, these would be expected to affect pain)
13. Cancer treatments that may interfere with stability of treatment (epidural, radiotherapy, chemotherapy, hormonal therapy)
14. Epilepsy
15. The patient is currently using or has used cannabinoid based medications within 30 days of study entry and is unwilling to abstain for the duration of the study
16. Positive urine drug screen for cannabinoids and other potential abuse substances (e.g. alcohol, cocaine, amphetamines and methamphetamines, hallucinogens, unprescribed opioids and ketamine, etc.)
17. Participation in another clinical trial within 30 days of enrolment in our trial