Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000877280
Ethics application status
Approved
Date submitted
24/04/2018
Date registered
23/05/2018
Date last updated
12/07/2022
Date data sharing statement initially provided
23/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1b clinical trial testing whether cimetidine prevents hearing loss from cisplatin chemotherapy in head and neck cancer patients
Scientific title
Phase Ib randomised, placebo-controlled, double-blinded trial using Cimetidine to prevent the Oto-, Nephro- and neuro-toxicity of Cisplatin by OCT2 inhibition in patients undergoing chemoradiation for head and neck cancer
Secondary ID [1] 294894 0
None
Universal Trial Number (UTN)
U1111-1212-8274
Trial acronym
CONCOCT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chemotherapy toxicity 307575 0
Condition category
Condition code
Cancer 306643 306643 0 0
Head and neck
Ear 306644 306644 0 0
Deafness
Neurological 306645 306645 0 0
Other neurological disorders
Renal and Urogenital 306646 306646 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will take cimetidine 800mg (2 x 400mg capsules) orally 30 minutes before, and again 90 minutes after, the start of each cisplatin infusion. This will be repeated every 3 weeks for 3 cycles of chemotherapy. The study medication will be administered under nursing supervision.
Intervention code [1] 301002 0
Treatment: Drugs
Comparator / control treatment
Patients will take 2 x placebo capsules (containing microcellulose) orally 30 minutes before, and again 90 minutes after, the start of each cisplatin infusion. This will be repeated every 3 weeks for 3 cycles of chemotherapy. The study medication will be administered under nursing supervision.
Control group
Placebo

Outcomes
Primary outcome [1] 305645 0
Mean change in hearing thresholds (averaged across 4000 Hz and 8000 Hz in both ears) between pretreatment baseline audiogram and an audiogram performed 3 months after completion of chemoradiation
Timepoint [1] 305645 0
3 months after completion of chemoradiation
Secondary outcome [1] 346017 0
Mean change in hearing thresholds (averaged for both ears) at each measured frequency between pretreatment baseline audiogram and an audiogram performed after each cycle of cisplatin
Timepoint [1] 346017 0
At 3 and 6 weeks after starting study treatment, and again 3 months after completing chemoradiation
Secondary outcome [2] 346018 0
Mean change in hearing thresholds (averaged across 4000 Hz and 8000 Hz in both ears) between pretreatment baseline audiogram and an audiogram performed 3 months after completion of chemoradiation, expressed as decibels lost per 100 mg/m2 of cisplatin
Timepoint [2] 346018 0
3 months post-chemoradiation
Secondary outcome [3] 346019 0
Proportion of patients with change in hearing loss categorised by Chang’s criteria and distortion-product otoacoustic emissions
Timepoint [3] 346019 0
3 months post-chemoradiation
Secondary outcome [4] 346020 0
Patient-reported outcomes for hearing, tinnitus and peripheral neuropathy, assessed as the proportion of patients who report the presence of, or treatment-emergent changes in, symptoms in these questionnaires: 1) the Tinnitus subscale for chemotherapy-induced neurotoxicity, 2) FACT/GOG neurotoxicity sensory subscale and 3) the Hearing Handicap Inventory for the Elderly
Timepoint [4] 346020 0
3 and 6 weeks from starting study treatment and 3 months post-chemoradiation
Secondary outcome [5] 346021 0
Renal injury from cisplatin as assessed by serial measurements of serum creatinine, magnesium and cystatin c, compared to baseline
Timepoint [5] 346021 0
3 and 6 weeks from starting study treatment and 3 months post-chemoradiation
Secondary outcome [6] 346022 0
Treatment-emergent adverse events (e.g. nausea, mucositis) graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events version 4.
Timepoint [6] 346022 0
3 and 6 weeks from starting study treatment and 3 months post-chemoradiation
Secondary outcome [7] 346023 0
Cumulative cisplatin dose administered over the duration of chemoradiation (expressed in mg/m2) assessed from medical records
Timepoint [7] 346023 0
End of study treatment (7 weeks after starting)
Secondary outcome [8] 346024 0
Radiation dose delivered (measured in Grays) as a proportion of that intended in the treatment plan for each patient, assessed from medical records
Timepoint [8] 346024 0
End of study treatment (7 weeks after starting)
Secondary outcome [9] 346025 0
Cumulative number of days on which radiation treatment was delayed, assessed from medical records
Timepoint [9] 346025 0
End of study treatment (7 weeks after starting)
Secondary outcome [10] 346027 0
Total radiation dose administered to the inner ear on each side calculated from the radiation treatment plan and final radiation doses administered, assessed from medical records
Timepoint [10] 346027 0
End of study treatment (7 weeks after starting)
Secondary outcome [11] 346030 0
Ratio of plasma unbound cisplatin and cimetidine concentrations at the end of the cisplatin infusion
Timepoint [11] 346030 0
At the end of the cisplatin infusion in Week 1
Secondary outcome [12] 352315 0
Mean change in hearing thresholds (as per the primary outcome) in cimetidine and control groups according to patient SLC22A2 genotype (of 11 single nucleotide polymorphisms tested)
Timepoint [12] 352315 0
After assessment of the primary outcome (i.e. at least 3 months after completion of treatment in all patients)

Eligibility
Key inclusion criteria
• pathologically-confirmed locally-advanced HNSCC for which concurrent chemoradiation using cisplatin 100mg/m2 every 3 weeks for 3 cycles is planned
• adequate baseline renal function (estimated glomerular filtration rate >60 ml/min)
• adequate baseline hepatic and bone marrow function;
• have signed written, informed consent
Minimum age
15 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• planned to receive platinum-based chemotherapy before or after radiation
• prior chemotherapy with cisplatin or platinum analogues
• existing hearing loss > 50 dB between 2000 and 8000 Hz, or hearing aids needed
• radiation treatment plan would result in a cochlear dose > 45 Gy in either ear
• allergic to cimetidine
• taking drugs that are substrates of OCT2 (organic cation transporter type 2) unless the medication can safely be omitted on each day of cisplatin and cimetidine administration
• taking medications with which cimetidine is known to have clinically-significant drug-drug interactions
• congenital or acquired long QT syndrome
• co-morbidities that would preclude cisplatin use, such as cardiac failure
• pregnant or breastfeeding.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Treatment allocation will be by sealed envelopes held by a central pharmacy (off-site)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Efficacy
Statistical methods / analysis
The expected acquired mean hearing loss at 4000 Hz and 8000 Hz (primary endpoint) in the placebo group is 20 dB. Using a two-sample comparison of means, a sample size of 30 randomised patients (15 in each arm) recruited over 2 years, with one dropout in each arm, gives the trial 90% power to detect a 5 dB difference in the mean hearing loss at these frequencies in the cimetidine group compared to the placebo group, with two-sided a=0.05. If up to 4 patients drop out of each arm the trial has 80% power to detect the specified difference in mean hearing loss.

The primary analysis will be based on an Intention-to-treat analysis. A per-protocol sensitivity analysis will also be conducted, excluding those patients not taking any cimetidine/placebo and evaluating mean change in hearing thresholds per 100 mg/m2 cisplatin administered.

The primary outcome is hearing loss at 4000 Hz and 8000 Hz averaged across both ears at 3 months post-CRT compared to baseline, and analysis will be by paired t test. A two-tailed p < 0.05 will indicate statistical significance.

All secondary analyses are hypothesis-generating, and no adjustments will be made for multiple comparisons. The secondary endpoints expressed as proportions will be reported as means, along with the mean differences, corresponding 95% confidence intervals and p-values, based on exact binomial distributions. Analyses will use t-tests to compare groups. For categorical outcomes chi-square tests will be used to compare groups. Adverse events in each arm will be tabulated and graded according to the NCI CTCAE version 4.03.

The mean ratio of unbound plasma cimetidine to cisplatin will be calculated and reported along with 95% confidence intervals. Repeated measures ANOVA will be used to analyse changes in renal function, hearing at individual frequencies and patient-reported outcomes over time.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/11/2018
Actual
15/08/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
16
Final
Recruitment outside Australia
Country [1] 10352 0
New Zealand
State/province [1] 10352 0
Auckland and Waikato

Funding & Sponsors
Funding source category [1] 299318 0
Charities/Societies/Foundations
Name [1] 299318 0
Cancer Research Trust New Zealand
Country [1] 299318 0
New Zealand
Primary sponsor type
Individual
Name
Associate Professor Michael Jameson
Address
University of Auckland Waikato Clinical Campus
Private Bag 3200
Hamilton 3240
Country
New Zealand
Secondary sponsor category [1] 298585 0
None
Name [1] 298585 0
Address [1] 298585 0
Country [1] 298585 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300226 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 300226 0
Ethics committee country [1] 300226 0
New Zealand
Date submitted for ethics approval [1] 300226 0
05/09/2018
Approval date [1] 300226 0
06/11/2018
Ethics approval number [1] 300226 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 51554 0
A/Prof Michael Jameson
Address 51554 0
University of Auckland Waikato Clinical Campus
Private Bag 3200
Hamilton 3240
Country 51554 0
New Zealand
Phone 51554 0
+64 7 839 8976
Fax 51554 0
+64 7 858 0940
Email 51554 0
[email protected]
Contact person for public queries
Name 51555 0
Navin Wewala
Address 51555 0
Palmerston North Hospital
50 Ruahine Street
Private Bag 11036
Palmerston North 4442
Country 51555 0
New Zealand
Phone 51555 0
+64 6 350 9159
Fax 51555 0
+64 6 350 8131
Email 51555 0
[email protected]
Contact person for scientific queries
Name 51556 0
Michael Jameson
Address 51556 0
University of Auckland Waikato Clinical Campus
Private Bag 3200
Hamilton 3240
Country 51556 0
New Zealand
Phone 51556 0
+64 7 839 8976
Fax 51556 0
+64 7 858 0940
Email 51556 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only
When will data be available (start and end dates)?
Immediately following publication, no end date
Available to whom?
Case-by-case basis at the discretion of Primary Investigator
Available for what types of analyses?
Only to achieve the aims in the approved proposal
How or where can data be obtained?
Access subject to approvals by Principal Investigator ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11458Study protocol  [email protected]
11459Statistical analysis plan  [email protected]
11460Informed consent form  [email protected]
11461Clinical study report  [email protected]
11462Ethical approval  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.