Inhaled Cannabis Versus Fentanyl Buccal Tablets for Management of Breakthrough Pain in Cancer Patients

• ClinicalTrials.gov Identifier: NCT03564548
• Recruitment Status: Not yet recruiting
• First Posted: June 21, 2018
• Last Update Posted: November 14, 2018
• Sponsor: Tetra Bio-Pharma
• Collaborator: Santé Cannabis
• Information provided by (Responsible Party): Tetra Bio-Pharma

Study Description

Brief Summary:

Breakthrough cancer pain (BTcP) is a rapid onset, high intensity and short duration pain episode, which takes place within a stable background pain control. It significantly affects the quality of life of oncologic patients and their ability to function normally. Rapid onset opioids are the standard treatment for BTcP, and the various fentanyl transmucosal formulations (FTF) are among the best examples of these treatments. However, the limited availability, the high cost, the complicated titration and the high risks of overdosing of FTF greatly challenge their use. In order to seek a potential alternative to FTF, the investigators are proposing to compare inhaled medical cannabis (PPP001) to FBT or placebo on relieving BTcP intensity in cancer patients.

Condition or disease	Intervention/treatment	Phase
Cancer; Breakthrough Cancer Pain	Combination Product: PPP001; Drug: FBT; Combination Product: Active PPP001 with FBT Placebo; Drug: Active FBT with PPP001 Placebo	Phase 2

Detailed Description:

This pilot study consists of two sub-studies:

1. An open-label randomized study to evaluate the effect of inhaled medical cannabis (PPP001) as compared to Fentanyl Buccal Tablets (FBT) to improve Pain Intensity (PI) in adult patients with breakthrough cancer pain (BTcP) and a stable opioid treatment for background pain:

   After proper screening and verified inclusion criteria, 20 consecutive patients will be recruited to participate in this initial study. After baseline assessments, patients will be randomized to one of 2 parallel groups:

   Group A: 10 patients will receive inhaled PPP001 for 2 weeks Group B: 10 patients will receive FBT for 2 weeks. During the first week of treatment, patients will be instructed to follow a specific titration regimen that will allow patients to optimize doses of PPP001 and FBT while adapting to the potential adverse events of both medications.

   Next, there will be a washout period of 1 week and a cross over will occur. Therefore, Group B will receive PPP001 and Group A will receive FBT for other 2 weeks.

   If the patient agrees and the physician investigator considers it is appropriate, a long-term follow-up of inhaled PPP001 for BTcP will be continued in an open-label fashion for the next 12 weeks.

2. A randomized double-blind placebo-controlled trial to evaluate the effect of inhaled PPP001 or FBT to improve PI when compared to placebo in another group of patients with BTcP:

After proper screening and verified inclusion criteria 40 consecutive patients will be recruited prospectively to participate in this trial. The same inclusion criteria of the open-label study will be applied with a different group of patients. After baseline assessments patients will be randomized to one of 2 parallel groups:

Group A: 4 weeks of PPP001 and fentanyl placebo buccal tablet (20 patients) Group B: 4 weeks of fentanyl buccal tablet and inhaled PPP001 placebo (20 patients) The inhalation of PPP001 or placebo will be allowed three times a day at 4-6 hours intervals. The use of previously prescribed rescue medication by treating physician will also be allowed. Patients will have a dose titration phase during the first week, followed by an additional 3-week period of treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The first part of the study will be in a crossover model and the second part in a parallel model
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Inhaled PPP001 Versus Buccal Tablets for the Management of Breakthrough Pain in Caner Patients: an Open Label, Crossover, Comparison Study Followed by a Randomized, Double-blind, Placebo-controlled Pilot Trial
• Estimated Study Start Date: December 1, 2018
• Estimated Primary Completion Date: June 30, 2019
• Estimated Study Completion Date: June 30, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Inhaled medical cannabis (PPP001); 280 mg dried cannabis pellet -(9% THC / 2% CBD per pellet) THC: Δ-9-tetrahydrocannabinol CBD: Cannabidiol	Combination Product: PPP001; Group assigned to PPP001 during the open-label
Active Comparator: Fentora Buccal Tablets (FBT); Fentora Buccal Product are composed of a potent opioid analgesic, intended for buccal mucosal administration. The tablets contain fentanyl citrate equivalent to fentanyl base and will be given in low-dose (100 mcg) or high-dose (200 mcg).	Drug: FBT; Group assigned to FBT during the open-label; Other Name: Fentora Buccal tablets
Experimental: Active PPP001 with FBT Placebo; Fentanyl Placebo tablets will have no fentanyl and will look identical to the active FBT. For these tablets there will also be low-dose tablets and high-dose tablets which will look identical to the active FBT 100 mcg and 200 mcg tablets.	Combination Product: Active PPP001 with FBT Placebo; Group assigned to active PPP001 in the randomized placebo-controlled trial; Other Name: Active PPP001 with Fentora Buccal tablets Placebo
Active Comparator: Active FBT with PPP001 Placebo; The placebo is designed to contain 0% Δ-9-tetrahydrocannabinol (THC) and as per the placebo specifications < 0.9% total Cannabidiol (CBD).	Drug: Active FBT with PPP001 Placebo; Group assigned to active FBT in the randomized placebo-controlled trial; Other Name: Active Fentora Buccal tablets with PPP001 Placebo

Outcome Measures

Primary Outcome Measures :

1. Breakthrough cancer pain intensity assessed by Pain Intensity (PI) measurement a numerical rating scale [ Time Frame: Changes from baseline PI at 60 minutes post PPP001 or FBT administration ]

   Pain Intensity (PI) measurement a Numerical Rating Scale (zero= no pain and 10= pain as bad as it can be).

   A reduction of PI ≥ 33% will be considered as a clinically important level of pain relief

Secondary Outcome Measures :

1. Patient's general impression (GI) of drug efficacy assessed by a verbal rating scale [ Time Frame: GI of drug efficacy will be measured at 60 minutes following the administration of PPP001 or FBT ]
   The patient's general impression (GI) of drug efficacy will be measured using a 5-point verbal rating scale ranging from 0=poor to 4=excellent
2. Cognition improvement assessed by Mini-Cog, a screening tool for Cognition [ Time Frame: Mini-Cog used at baseline, at week 2 and week 5 of the open-label, crossover comparison study and at week 1 and week 4 follow-up of the randomized placebo-controlled trial ]
   Using the Mini-Cog, a simple and effective instrument with excellent screening characteristics, that compared to other cognitive tools, takes less time to be performed. This test consists of a delayed three-word recall (0-3 points) and a clock drawing test (0-2 points). It was developed for the community care setting, takes three to five minutes to complete, and education or language do not seem to importantly influence test results. A cut point of < 4 points will suggest cognitive impairment in this population
3. Mood improvement assessed by the Profile of Mood States [ Time Frame: Both questionnaires will be done at baseline, at week 2 and week 5 of the open-label, crossover comparison study and at week 1 and week 4 follow-up of the randomized placebo-controlled trial ]
   Using the Profile of Mood States (POMS), which is a self-administered questionnaire designed to assess current mood states through six bipolar scales: elated/depressed, composed/anxious, energetic/tired, agreeable/hostile, confident/unsure, and clear-headed/confused.
4. Quality of life improvement assessed by the European Organization for Research and Treatment (EORTC) of Cancer Quality of Life Questionnaire (QLQ-C30) [ Time Frame: This will be performed at baseline, at week 2 and week 5 of the open-label, crossover comparison study and at week 1 and week 4 follow-up of the randomized placebo-controlled trial. ]

   European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for cancer (QLQ-C30). This is a 30-item core-cancer specific questionnaire integrating system for assessing Health Related quality of Life (HRQoL) of cancer patients participating in international clinical trials. The questionnaire incorporates five functional scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), a global health and QOL scale, and single items for the assessment of additional symptoms commonly reported by cancer patients (e.g., dyspnea, insomnia, appetite loss, constipation, and diarrhea), as well as the perceived financial impact of the disease and treatment.

   All items are scored on 4-point Likert scales, ranging from 1 ("not at all") to 4 ("very much"), with the exception of two items in the global health/ QOL scale which use modified 7-point linear analog scales

5. Effects of PPP001 on concurrent medications compliance [ Time Frame: This will be done at baseline, at week 2 and week 5 of the open-label, crossover comparison study and at week 1 and week 4 follow-up of the randomized placebo-controlled trial. ]
   Changes in concurrent medications will be measured using the Medication Quantification Scale (MQS) version III. The MQS version III is a method of quantifying different pain drug regimens by evaluating the use of 22 distinct drug classes (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], antidepressants, benzodiazepines, opiates). A single value is calculated based on a patient's pain medication profile, taking into account dosages, and the types of pain medications prescribed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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. Confirmed diagnosis of cancer with life expectancy of more than 3 months; Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
5. Background cancer pain stable (pain lower or equal to 4/10 on numeric rating scale) and adequately controlled with oral morphine, oxycodone, hydromorphone or transdermal fentanyl.
6. Patient receiving at least 60 mg and no more than 1000 mg of oral morphine equivalent daily doses (MEDD).
7. The patient has a clinical diagnosis of breakthrough cancer pain with lower or equal to 4 episodes per day but higher or equal to 3 episodes per week.
8. The patient is using no more than one type of breakthrough opioid analgesia.
9. Normal cognitive status according to MiniCog
10. Normal liver function (defined as aspartate aminotransferase 10-40 U/L and alanine aminotransferase 7-56 U/L)
11. Normal renal function (defined as serum creatinine level lower than 133 µmol/L and Estimated Glomerular Filtration Rate (eGFR) higher or equal to 60)
12. 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
13. Ability to read and respond to questions in French or English.

14. 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.

    If of non-childbearing potential - should be surgically sterile or in a menopausal state

15. A male volunteer with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must be surgically sterile or agrees to use one of the accepted contraceptive regimens from first drug administration until 3 months after the last drug administration.

Exclusion Criteria:

1. Breakthrough pain due to other causes different than cancer related pain
2. Previous serious adverse event or hypersensitivity to cannabis or cannabinoids, fentanyl, other opioids or its excipients
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. Impaired respiratory function that may severely increase the risk of clinically relevant respiratory depression by breakthrough cancer pain fentanyl treatment
6. Recent treatment with mono-amine oxidase inhibitors for the last 2 weeks
7. Use of methadone in the last 30 days
8. Current substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM 5)
9. Life-time history of dependence on cannabis or diagnosis of cannabis use disorder (CUD) according to the DSM 5
10. Life-time history of DSM 5 schizophrenia, bipolar disorder, or previous psychosis with or intolerance to cannabinoids
11. Current suicidal ideation according to the Columbia-Suicide Severity Rating Scale (C-SSRS)
12. 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
13. Hepatic impairment (aspartate aminotransferase more than three times normal) or renal function impairment (serum creatinine level higher to 133 µmol/L, Estimated Glomerular Filtration Rate (eGFR) lower to 60)
14. Cognitive impairment according to MiniCog
15. Patient has any planned clinical interventions that would affect their breakthrough cancer pain within the 5 or 4 weeks of the 2 components of the study (e.g., chemotherapy or radiation therapy where, in the clinical judgment of the investigator, these would be expected to affect breakthrough cancer pain)
16. Cancer treatments that may interfere with stability of treatment (interventional pain management, radiotherapy, chemotherapy, hormonal therapy)
17. Epilepsy
18. The patient is currently using or has used cannabis or cannabinoids in any form within 90 days of study entry and is unwilling to abstain for the duration of the study. If the patient is an occasional cannabis user (cannabis use in any form: 1-3 times/week) he or she must agree to a 7-day washout period where they will refrain from any cannabis use. After 1-week of cannabis abstinence, THC blood levels will be verified, and results must be negative, or the patient will be excluded from the study.
19. Positive urine drug screen for cannabinoids and other potential abuse substances (e.g. alcohol, cocaine, amphetamines and methamphetamines, un-prescribed opioids)
20. Participation in another clinical trial within 30 days of enrolment in our trial

Contacts and Locations

Contacts

Contact: Cynthia El Hage, Ph.D; (514) 419-4131 ext 1014; cynthia.el.hage@tetrabiopharma.com

Contact: Guy Chamberland, MSc, PhD; 5142209225; guy@tetrabiopharma.com

Locations

Canada, Quebec

Sante Cannabis

Montréal, Quebec, Canada, H2L 3K9

Sponsors and Collaborators

Tetra Bio-Pharma

Santé Cannabis

Investigators

• Principal Investigator: Antonio Vigano, MD, MSc; McGill University
• Study Director: Erin Prosk, MSc; Santé Cannabis

More Information

• Responsible Party: Tetra Bio-Pharma
• ClinicalTrials.gov Identifier: NCT03564548 History of Changes
• Other Study ID Numbers: PPP001-Ph2-F01
• First Posted: June 21, 2018
• Last Update Posted: November 14, 2018
• Last Verified: November 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cancer Pain; Breakthrough Pain; Pain; Neurologic Manifestations; Signs and Symptoms; Fentanyl; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adjuvants, Anesthesia; Anesthetics, Intravenous; Anesthetics, General; Anesthetics