ISRCTN - ISRCTN68734605: Assessing the potential of ivabradine and related drugs for the treatment of nerve pain in patients

Plain English Summary

Background and study aims
Neuropathic pain is pain that arises because of nerve damage. Nerves can be damaged by accidental trauma or inadvertently by surgery. Diseases like diabetics or shingles can also cause nerve damage. Not every patient who has nerve damage experiences pain, but those who do suffer from long-term pain that is very challenging and difficult to treat. Scientists in Cambridge have discovered that HCN-2 receptor contributes to pain caused by nerve damage in the laboratory. Drugs have yet to be developed that block the HCN-2 receptor specifically. However, there is already a drug licensed that blocks all types HCN receptors (HCN 1 to 4) called ivabradine. It is currently used to treat patients who have chest pain for heart disease by slowing heart rate. The aim of this study is to find out what effect taking ivabradine has on pain levels in people with neuropathic pain

Who can participate?
Adults with neuropathic pain and no heart problems.

What does the study involve?
All participants receive ivabradine tablets to take twice a day starting at a dose of 2.5mg. The does is then increased every 2-3 weeks if there are no side-effects until the maximum dose of 7.5mg twice a day is reached. Depending on participants’ reaction to the medication, the study lasts for between 14 and 28 days. Every day while they are taking part, participants are asked to rate their pain levels to see if the drug has had any effect.

What are the possible benefits and risks of participating?
There are no direct benefits for patients however this study will help improve understanding about whether HCN channels contributes to nerve pain in humans. The main side effect of ivabradine is slowing of heart rate and so the dose used will be carefully controlled depending on heart rate.

Where is the study run from?
Addenbrookes Hospital (UK)

When is the study starting and how long is it expected to run for?
December 2015 to March 2019

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Dr Michael Lee
ml404@cam.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Dr Michael Lee

ORCID ID

http://orcid.org/0000-0002-5838-2916

Contact details

Box 93
University Division of Anaesthesia
Addenbrooke's Hospital
Cambridge
CB2 0QQ
United Kingdom
+44 1223 217888
ml404@cam.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

32107

Study information

Scientific title

The role of HCN channel receptor in neuropathic pain: An open-label, single arm study of ivabradine in patients with peripheral neuropathic pain

Acronym

HCN-pain

Study hypothesis

The primary hypothesis being tested is that a reduction from baseline in averaged pain scores after treatment with ivabradine in patients with peripheral neuropathic pain.

Ethics approval

London - Bromley Research Ethics Committee, 07/12/2016, ref: 16/LO/1901

Study design

Non-randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Anaesthesia, perioperative medicine and pain management, Primary sub-specialty: Anaesthesia, Perioperative Medicine and Pain Management; UKCRC code/ Disease: Neurological/ Nerve, nerve root and plexus disorders

Intervention

All participants receive oral administration of Ivabradine. The dosage of ivabradine will range from 2.5 mg to 7.5 mg twice daily. The starting dose is 2.5mg twice daily for all participants, if tolerated, the dose will be increased every 2-3 weeks by increments of 2.5mg twice daily to a maximum of 7.5mg twice daily.

The study comprises the following visit types
1. Screening
2. Drug initiation
3. Dose adjustments (maximum of 2 occasions)
4. Dose cessation
5. Follow-up

The interval between Screening and Drug Initiation is between 14-28 days. The interval for visit types is 14-21 days. Ivabradine treatment duration is twelve weeks maximum. Dose range is 2.5 to 7.5 mg twice daily.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Daily Pain: Numerical ratings (0=no pain, 10= worst possible pain) scores, recorded daily, starting measured 2 weeks prior to dose initiation till follow-up.

Secondary outcome measures

The following measures are obtained once per visit starting the day before the dose initiation:
1. Overall Pain (between visits) is measured using the Brief Pain Inventory-SF (BPI) questionnaire
2. Sleep is measured using the Insomnia Severity Index (ISI) questionnaire
3. Physical function is measured using the Pain Disability Index (PDI) questionnaire
4. Neuropathic pain sensations are measured using the Neuropathic Pain Symptom Inventory (NPSI) questionnaire
5. Mood is measured using the Depression, Anxiety and Positive Outlook Scale (DAPOS) questionnaire
6. Skin sensitivity is measured using the Sensory scores with punctate and brush stimuli

Overall trial start date

01/12/2015

Overall trial end date

30/03/2019

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Able to give voluntary written informed consent to participate
2. Aged 18 years and above
3. Have peripheral neuropathic pain from diabetes, herpes zoster infection, or trauma to peripheral nerve trunks/plexus (from surgery or physical injury) and DN4 score ≥ 4
4. Have pain for 6 months or more
5. Have pain rated > 4 on a numerical rating scale (NRS) (0= No pain; 10= pain as bad as you can imagine) on at least one Pain sub-item from Brief Pain Inventory
6. Be registered with a GP
7. Have the following findings on standard ECG at screening:
7.1. Normal sinus rhythm (measured for 1 minute on lead II)
7.2. PR interval ≤ 210 ms
7.3. QTcB ≤ 430 ms for men and QTcB ≤ 450 ms for women
7.4. QRS duration ≤ 120 ms
7.5. Heart rate ≥ 60 beats per minute

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 50; UK Sample Size: 50

Participant exclusion criteria

1. Known to be allergic to ivabradine or have hypersensitivity to any of the formulation ingredients
2. Current treatment with ivabradine
3. Use of drugs with potential serious interactions with Ivabradine – as indicated by the latest version of British National Formulary at the time of screening
4. Currently receiving or have received prior to the screening (Visit 1) any of Prohibited Concomitant Medications
5. Have pain rated = 10 a numerical rating scale (NRS) (0= No pain; 10= pain as bad as you can imagine) on ALL pain sub-items from Brief Pain Inventory
6. Scheduled for clinical treatment (e.g. drugs, psychological therapy, surgical or interventional treatment) for any chronic pain or other health condition for the anticipated duration of the study
7. New York Heart Association heart failure class II or higher, or hospitalization for heart failure within a year
8. Myocardial infarct, coronary revascularization, stroke or transient ischemic attack within 6 months of the screening visit
9. Transplanted heart, implanted pacemaker, implantable cardioverter defibrillator or cardiac resynchronization therapy
10. Scheduled for coronary revascularization; or likely to require cardiac surgery for valvular disease
11. Known congenital long QT, permanent atrial fibrillation or flutter, sick sinus syndrome, sinoatrial block, second and complete atrio-ventricular block
12. Severe or uncontrolled hypertension with systolic BP > 180mmHg or diastolic BP > 110 mmHg after sitting for at least 5 minutes
13. Sitting systolic BP < 85mmHg or symptomatic hypotension
14. Active uncontrolled psychiatric illness (e.g. severe depression (risk of self-harm), schizophrenia, substance misuse or dependence)
15. Known severe renal disease, or moderate or severe liver disease
16. Known to be HIV, Hepatitis B or C seropositive (Level 3 containment laboratory procedures are not available for the handling of infectious specimens)
17. Any illness or condition that in the opinion of the PI or delegated investigators, precludes safe participation in the Study or interferes with Study procedures.
18. Currently participating in any interventional Study, have participated in an interventional Study within 12 weeks of screening or are currently enrolled in a non-interventional Study, which participating in this Study would impact upon
19. Unwilling for the GP to be notified or to provide information relevant to the participation of the clinical Study
20. Transaminases ALT and AST greater than three times the upper normal limit
21. Haemoglobin <11.0g/dL
22. Creatinine clearance (Cockcroft-Gault – section 21.4 of the protocol) < 50 ml/min/1.73m2
23. Females of childbearing potential who decline to use adequate contraceptive measures for the duration of the study
24. Pregnant or breast feeding

Recruitment start date

03/04/2017

Recruitment end date

03/10/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Addenbrookes Hospital
Cambridge University Hospitals NHS Foundation Trust Hills Road
Cambridge
CB2 0QQ
United Kingdom

Sponsor information

Organisation

Cambridge University Hospitals NHS Foundation Trust

Sponsor details

Box 277
Addenbrookes Hospital
Cambridge
CB2 0QQ
United Kingdom
+44 1223 256407
r&denquiries@addenbrookes.nhs.uk

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Research council

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location