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Report for Clinical Trial NCT02720822

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Pragmatic, Phase III, Multi-site, Double-blind, Placebo Controlled, Parallel Arm, Dose Increment Randomised Trial of Regular, Low Dose Extended Release Morphine for Chronic Refractory Breathlessness

Breathlessness is an overwhelming symptom affecting tens of thousands of Australians every day. For many people, it persists even when all the underlying causes have been optimally managed (chronic breathlessness). In these circumstances, it often occurs at rest or with minimal exertion. Evidence from a number of clinical studies suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, it is not well established which patients derive more benefit and what is the net clinical effect of this treatment (weighing benefits and harms). This is a phase III, multi-site, randomised, double-blind, placebo-controlled trial with patients with chronic obstructive pulmonary disease (COPD) and severe chronic breathlessness which will explore several important questions: - Are regular, low doses of morphine at four possible doses over 3 weeks more effective than placebo at improving breathlessness? - Does increasing the dose in people who already are experiencing some benefit provide even greater reduction in worst breathlessness? - Does the medication have any effect on daily activity and quality of life? - What are the common or serious side effects of this intervention? - Does the benefit from the medication outweigh the side effects it produces? - Are there specific characteristics of people who are more likely to receive benefit from extended release morphine? Participants will receive once daily extended release morphine (plus laxative, docusate with senna), or placebo (placebo laxative) in addition to their usual medication for up to 3 weeks at increasing doses. Participants will have a medical interview and physical examination to collect some general health information, and baseline measurements including; daily activity, symptoms, and quality of life. A small amount of blood may be required to check eligibility. Further blood samples may be taken at week 1 and 3 to enable testing on how individuals respond to opioids, further consent will be obtained for these samples. Data on benefits, side effects, and medical care will be collected during comprehensive weekly visits. Participants will also fill out a simple diary twice daily for weeks one to three of the study, and for one day each week during an optional 6 month extension stage. The outcome of this study may enable better management of symptoms and activity in people COPD with medicines that are shown to be effective and safe.

NCT02720822 Chronic Obstructive Pulmonary Disease Dyspnea
MeSH:Lung Diseases, Obstructive Pulmonary Disease, Chronic Obstructive Dyspnea
HPO:Chronic obstructive pulmonary disease Dyspnea Obstructive lung disease Respiratory distress

5 Interventions

Name: Placebo

Description: Treatment with placebo is given as one double-blind capsule in the morning.
Type: Drug
Group Labels: 4

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Placebo

Name: Morphine Sulfate

Description: Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Type: Drug
Group Labels: 11

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Morphine sulfate (16, 16, 16 mg) Morphine sulfate (16, 16, 24 mg) Morphine sulfate (16, 24, 24 mg) Morphine sulfate (16, 24, 32 mg) Morphine sulfate (8, 16, 16 mg) Morphine sulfate (8, 16, 24 mg) Morphine sulfate (8, 8, 16 mg) Morphine sulfate (8, 8, 8 mg)

Name: Plus laxative (Docusate with senna)

Description: If patients are taking morphine, a laxative will be offered. This applies whatever the dose of morphine being taken (8mg, 16mg, 24mg or 32 mg).
Type: Drug
Group Labels: 12

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Mo Morphine sulfate (16, 16, 16 mg) Morphine sulfate (16, 16, 24 mg) Morphine sulfate (16, 24, 24 mg) Morphine sulfate (16, 24, 32 mg) Morphine sulfate (8, 16, 16 mg) Morphine sulfate (8, 16, 24 mg) Morphine sulfate (8, 8, 16 mg) Morphine sulfate (8, 8, 8 mg)

Name: Plus placebo laxative

Description: If the patients are taking placebo, a placebo laxative will be offered.
Type: Drug
Group Labels: 4

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Placebo

Name: FitBit charge HR (Accelerometer)

Description: A Fitbit will be worn by patients during week 1 and week 3.
Type: Device
Group Labels: 12

Morphine Sulfate (0, 0, 8 mg) Morphine sulfate (0, 8, 16 mg) Morphine sulfate (0, 8, 8 mg) Morphine sulfate (16, 16, 16 mg) Morphine sulfate (16, 16, 24 mg) Morphine sulfate (16, 24, 24 mg) Morphine sulfate (16, 24, 32 mg) Morphine sulfate (8, 16, 16 mg) Morphine sulfate (8, 16, 24 mg) Morphine sulfate (8, 8, 16 mg) Morphine sulfate (8, 8, 8 mg) Placebo


Primary Outcomes

Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, Stage1-3 (daily diary) and Stage 4 (weekly diary). The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week1) The difference of morphine sulphate 16 mg and placebo (end of week 1)

Measure: Change from baseline worst breathlessness intensity over the previous 24 hours

Time: Week 1

Description: Difference from the baseline in the number of steps per day measured using the Fitbit(Charge HR). Measured at baseline, end of week 1, and end of week 3. The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week 1) The difference between morphine sulphate 16mg and placebo (end of week 1) Comparison between baseline and end of week 3

Measure: Change from the baseline in the number of steps per day

Time: Week 3

Secondary Outcomes

Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Stages 1-4.

Measure: Change from baseline end-tidal carbon dioxide

Time: Up to week 15

Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Concomitant use of oxygen will be recorded. Stages 1-4.

Measure: Change from baseline pulse oximetry

Time: Up to week 15

Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Measure: Change from baseline intensity of breathlessness "average"

Time: Up to week 15

Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Measure: Change from baseline distress from breathlessness over the previous 24 hours

Time: Up to week 15

Description: Chronic Respiratory Questionnaire - Dyspnoea and Mastery Subscales. Baseline and end of Weeks 1-3.

Measure: Change from baseline perceived-impact of breathlessness

Time: Up to week 3

Description: Rated on the Modified Medical Research Council Breathlessness Scale (mMRC). Measured at baseline and at the conclusion of the study.

Measure: Change from baseline functional impact of breathlessness

Time: Up to week 15

Description: Measured using the Fitbit(Charge HR). Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline sleep minutes

Time: Week 3

Description: Measured using the Fitbit(Charge HR). Given in number of movements per night (e.g. rolling over). Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline sleep activity

Time: Week 3

Description: Measured using the Fitbit(Charge HR). Difference from baseline in the number of active minutes per day. Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline in activity levels

Time: Week 3

Description: Measured using the Fitbit(Charge HR). Difference from baseline number of calories spent per day. Assessed at baseline (2 days), weeks 1 and 3.

Measure: Change from baseline total energy expenditure

Time: Week 3

Description: Measured using Australian-modified Karnofsky Performance Status (AKPS). Baseline, Stage1, Stage2, Stage3 and Stage 4.

Measure: Change from baseline performance status

Time: Up to week 15

Description: Measured using Barthel Index. Baseline and Stage 4.

Measure: Change from baseline activities of daily living

Time: Up to week 15

Description: Rated on a 4 point Likert scale. Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Measure: Change from baseline in sleep quality

Time: Up to week 15

Description: Thirty (30) participants at the Sydney and Adelaide sites will be invited to undertake a simple, non-invasive home sleep study using the ResMed ApneaLink Plus device. Baseline and Stage3.

Measure: Change from baseline in objective sleep testing

Time: Week 3

Description: Up to ten (10) participants will also undergo two (baseline and Stage 1) in-laboratory overnight sleep studies in Sydney and Adelaide.

Measure: Change from baseline Polysomnography

Time: Week 3

Description: Twenty (20) participants in Adelaide and Sydney. Baseline and on day 2 and 7 of the first week in an office-based simulator - AusEd.

Measure: Change from baseline Driving ability

Time: Week 3 + 2 days

Description: The baseline blood samples will be analysed to detect the presence of UGT2B7*2 and *28 polymorphisms.

Measure: Pharmacogenetic opioid profile - Number of participants with UGT2B7*2 and *28 polymorphisms

Time: Baseline (1 day)

Description: The baseline blood samples will be analysed to detect the presence of P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)

Measure: Pharmacogenetic opioid profile - Number of participants with P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)

Time: Baseline (1 day)

Description: The baseline blood samples will be analysed to detect the presence of 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism

Measure: Pharmacogenetic opioid profile - Number of participants with 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism

Time: Baseline (1 day)

Description: The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism

Measure: Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism

Time: Baseline (1 day)

Description: In a subset of 55 participants, morphine peak plasma concentrations will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Peak Plasma Concentration [Cmax]

Time: Week 1

Description: In a subset of 55 participants, morphine AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Area Under the Curve (AUC)

Time: Week 1

Description: In a subset of 55 participants, M6G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Peak Plasma Concentration [Cmax]

Time: Week 1

Description: In a subset of 55 participants, M6G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Area Under the Curve (AUC)

Time: Week 1

Description: In a subset of 55 participants, M3G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Peak Plasma Concentration [Cmax]

Time: Week 1

Description: In a subset of 55 participants, M3G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Area Under the Curve (AUC)

Time: Week 1

Description: Baseline and study completion. To explore whether longer term morphine treatment is associated with decreased levels of testosterone.

Measure: Change from baseline serum testosterone level

Time: Week 15

Description: Rated on a Lickert Scale. Baseline, weeks 1-3 (daily diary), Stage 4 (weekly diary): Includes constipation, anxiety, appetite, nausea, vomiting, drowsiness, difficulty thinking clearly, problems passing urine, itch, other symptoms.

Measure: Adverse Effects

Time: Up to 15 weeks

Description: Measured using the Edmonton Symptoms Assessment Scale (ESAS)

Measure: Change from baseline in concurrent symptoms

Time: Up to 15 weeks

Description: Rated using the Hospital Anxiety and Depression Scale (HADS). At baseline, completion of randomization stage and study exit.

Measure: Change from the baseline anxiety and depression

Time: Up to Week 15

Description: Participant-rated 7 point scale of the perception of their change, specifically their improvement since the commencement of the study. Measured at the end of Stages 1-3 and conclusion.

Measure: Change in baseline global impression of change

Time: Up to 15 weeks

Description: Measured with EQ-5D-5L questionnaire. Baseline, Stages 1-3, Stage 4, conclusion.

Measure: Change from baseline health-related quality of life

Time: Up to 15 weeks

Description: Measured with the COPD Assessment Test (CAT) Baseline, Stages 1-3, Stage 4 and conclusion.

Measure: Change from baseline health-status in COPD

Time: Week 3

Description: Asked at the end of week 1 and at the conclusion/drop-out of the study. A 3-point Likert scale will be used.

Measure: Blinded-patient preference to continue the treatment [3-point Likert Scale]

Time: Up to week 15

Description: Scored using the Zarit Burden Interview (ZBI) 12 item short-form questionnaire. Baseline, end of weeks 1-3, stage 4.

Measure: Change from baseline caregiver Impact

Time: Up to week 15

Description: From randomisation to 28 days post treatment or death (whichever is the shorter period). Estimated based on all health-care contacts including length of hospitalizations, emergency department visits, DRG codes, community health visits, GP and community nurse visits, outpatient visits and date of death. These participant level data allow within trial modeling using bootstrapping methods of replicates for costs and consequences of alternative strategies, allowing for covariance between costs and effects. Incremental net monetary benefit and cost-effectiveness acceptability curves will be estimated at potential threshold values for an additional responder.

Measure: Economic Evaluation - Cost per responder

Time: Up to week 4

Description: Evaluation using the Subjective Opioid Withdrawal Scale (SOWS) for 3 consecutive days. After the completion of the study (Weeks 1-15).

Measure: Opioid Withdrawal

Time: Up to week 15 + 3 days

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 A118G

Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism. --- A118G ---

The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism. --- A118G ---



HPO Nodes


HPO:
HP:0002094: Dyspnea
Genes 456
IFT52 CCDC103 COL2A1 GATA6 KCNA1 SRP54 DNAAF2 TET2 TGFB2 CPT2 VCL OPTN RRM2B SCN4A EDN1 SPINK1 DISC1 VPS33A LRRC56 FOXF1 DPM1 STN1 GYG1 LAMC2 NKX2-1 DNAH11 FOXP3 TRPV6 CAV1 ORC1 SETBP1 IRAK1 PPARGC1A GBA HYDIN SLC2A10 SCN1B DNAH9 SQSTM1 CYB5R3 DNASE1L3 COX10 DNAH5 GNAS LRP4 TRNK PRRT2 MRPL3 DNAH1 ALDH7A1 DNAI1 ORC6 CSPP1 COL1A2 SLC5A7 RSPH3 CLCNKB LOX TGFBR2 FASTKD2 CTRC FAM13A SFTPC EFEMP2 UBQLN2 SLC52A3 CCDC39 MAPT SDCCAG8 FUS ACADM OTX2 FGFR2 FBP1 DNAJC21 MATR3 ND3 RAPSN FBN1 NKX2-1 SFTPA2 COX6B1 SMPD1 NDUFB11 CHRNA1 FGFR2 NDUFB8 COX7B COX8A EIF2AK4 FIG4 HLA-DRB1 FBLN5 ARMC4 CHMP2B TSC1 MMAA STAT3 SSR4 LYRM4 CYB5A POLG2 TSC1 ZIC3 STT3B C1R MYL3 FBP1 MPC1 LDLRAP1 HLA-DRB1 SLC25A4 ATXN2 CHRNE ACVRL1 GLA ABCG8 TRMU GNAS LAMB2 CFTR CCDC151 USP9X LAMA3 IRF2BP2 ND1 VCP IL1RN FGFR2 ND6 BCOR ETFA ND2 POMT1 TERT CHRND ALAS2 BMPER CDC6 SCO2 DRC1 WAS STK36 TRMT5 GBA LIFR SH2B3 FAM20C TRNS1 RPGR NDUFS2 VCP TGFB3 DNAL1 CFAP298 RPS28 TET2 ZBTB16 NUMA1 DCTN1 DNAAF1 CSF2RB SMAD4 TRNE TAF15 ACADVL GAS2L2 AGRN SNAP25 CSF2RA FGFR2 STAT5B DNAAF5 GBA C1QA PON1 TTC25 SLC25A1 DNAAF3 PMM2 MMUT MEGF10 CCR6 FLNC SLC35A1 CCN2 DYNC2LI1 PRPH EPHB4 MMUT HLA-DRB1 STAT5B TRNV DMPK SLC18A3 SOX9 SBDS COX14 KCNJ6 NABP1 TREM2 CHRNB1 SMAD3 GTPBP3 MUSK WIPF1 DSC2 DOK7 TRNN PFN1 MCIDAS RARA C9ORF72 HLCS CCDC40 PET100 EP300 NKX2-5 SCN4A SCN4A ENG CHAT CHRNB1 SOD1 GLT8D1 CRELD1 DNAJB13 TRNW SCNN1B ANG GLE1 NEK1 PIGT SCNN1A COL2A1 APOB ZFPM2 RSPH4A NGLY1 COLQ FOXE3 TRAK1 ATRX CCNO NPM1 VAMP1 LGI4 PLCB4 MYBPC3 NR2F2 CNTNAP1 NDUFAF3 ELN SCN5A COPA TK2 SLC25A3 CHAT SLC12A3 CYB5R3 ETFDH AIMP2 PRKAR1A CRLF1 COA8 GAA SCO2 TBX4 FIP1L1 UBE3B DNAI2 ND4 LAMB3 TACO1 SPAG1 CHRNE TWNK PML SFTPC XYLT1 TBL1XR1 SFTPA2 JAK2 TARDBP ISCU MARS1 MYH11 RPS26 STX16 COX20 GATA6 RTEL1 TERT ERF SCNN1G PNKD TERC SFTPB SERPING1 DPM2 GNAS PRKCSH DNA2 SURF1 MAPT NME8 DNAAF4 FGFR1 EFTUD2 UNC13A CHRND NOD2 TBK1 ADAMTS13 PARN PRRX1 CFAP410 BMPER RSPH1 VAPB ARX DBH CCNF TRPM4 CCDC114 GNAI3 TUBB4A ATP11A CAV1 COQ7 TBC1D24 GATA4 TSC2 NAGS DPP9 ITGA3 PRSS1 BMPR2 CFAP300 ERBB4 ADNP MFAP5 EPOR MYO9A TRNL1 ORC6 AGRN SPEF2 PRRX1 CDC45 MAT2A RUNX2 MYH11 SFTPA1 LDLR POLG TRIP11 OFD1 PRKAR1A FOXJ1 MYL2 ZMYND10 CHRNE PLEC SFTPC MGME1 MYLK NEB USP9X COA8 TRIP11 HBB GMNN TSC2 CASR ORC4 ND5 DSP STAT4 NUP214 TRNE HLA-B MGME1 DNAAF3 DNA2 RSPH9 ABCA3 BTNL2 NEFH IFT81 COL2A1 LTBP3 IKZF1 KAT6A KLHL7 DAO SCN5A RNU4ATAC SCO1 PUF60 DNAJB6 ATP6 HCCS TNNC1 PON3 BTNL2 ADCY6 DMPK CFAP221 COL13A1 DNAAF6 AK9 STT3B PGM1 ACTA2 CHCHD10 PRKG1 TTN TGFBR1 MUC5B SERPINA1 IRF5 ABCA3 HNRNPA1 COL13A1 NPPA SIK1 GATA6 SPP1 CHRNA1 CSF2RB ORC1 NAGS EPHA4 EDA LRRC6 MUC5B PON2 COL2A1 GAS8 MMAB SYT2 EOMES SLC25A1 JPH2 PCSK9 ANXA11 AIFM1 VPS33A DPM2 ABCG5 CDT1 CREBBP ETFB TRNK CCDC65
Protein Mutations 0
SNP 0