Condition category
Nervous System Diseases
Date applied
09/09/2016
Date assigned
12/09/2016
Last edited
12/09/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
The number of people with diabetes is growing rapidly in the UK and is predicted to increase from 3.2 million in 2013 to 5 million by 2025. People living with diabetes often have to live with long-term complications of the disease. One of these complications is diabetic peripheral neuropathy, where the nerves in the arms and legs become damaged, leading to painful symptoms. One quarter of all people with diabetes experience these symptoms, known as “painful diabetic neuropathy”. Patients may present with burning, aching or “electric-shock” type pains. In some patients normal touch by day time or bed clothes can cause severe pain as the skin becomes extremely sensitive to touch. As the pain is felt every day, patients may have difficulty doing simple daily activities such as walking to the shop or socializing with friends. This results in a poor quality of life and depression. Unfortunately current individual medications provide only partial benefit in around of half of all patients, with many enduring inadequate pain relief and unwanted reactions. Not surprisingly therefore, many patients are frustrated with not being able to work and too many visits to see the doctor. The negative impact on them, their families and the NHS is considerable. The National Institute for Heath and Care Excellence (NICE) recommends a choice of four drugs; amitriptyline, duloxetine, and pregabalin or gabapentin, as initial treatment for painful diabetic neuropathy. If the initial treatment is not fully effective NICE recommends adding one of the other drugs in combination with the first drug. The aim of this study is to find out which of these drugs is the most effective initial treatment and then the best additional treatment for patients with painful diabetic neuropathy.

Who can participate?
Adults with painful diabetic neuropathy

What does the study involve?
Participants are randomly allocated to receive the three treatment pathways in a different order. The first pathway involves taking amitriptyline for six weeks and then amitriptyline in combination with pregabalin for a further 10 weeks (if amitriptyline alone is not giving effective relief). The second pathway involves taking duloxetine for six weeks and then duloxetine in combination with pregabalin for a further 10 weeks (if necessary). The third pathway involves taking duloxetine for six weeks and then pregabalin in combination with amitriptyline for a further 10 weeks (if necessary). The total length of the study for each patient will be one year. During this period patients will be contacted by telephone and seen in hospital on multiple occasions. Study medications will be started at a low dose and increased gradually to find the right dose for each individual patient. Throughout the study, response to treatment will be measured using pain diaries which patients will be asked to complete. Participants also complete questionnaires at the start of the study and after 6 and 16 weeks of each treatment pathway the measure quality of life, mood, sleep and reactions to the drugs.

What are the possible benefits and risks of participating?
Possible benefits of the study are that participants will be contacted weekly by the study nurse during the study, and will be seen in clinic regularly, so are likely to have more follow-up than normal. Participants may also find a treatment pathway that is effective in treating their painful diabetic neuropathy. When the study is complete, participants will be advised which order they received the treatments, so that they are able to request their preferred treatment from their care team going forward. Possible risks are that participants will be required to stop all current pain medication before starting the study and between each pathway will need to stop taking the study medication. The amount of time without any treatment will be short but if concerns should be discussed with the study team. Also, taking part in this research may mean additional appointments at the hospital, compared to the number of appointments received normally. Although this means extra travel, travel costs in attending these hospital appointments will be reimbursed if required.

Where is the study run from?
Eight hospitals clinics and 80 GP practices across England (UK)

When is the study starting and how long is it expected to run for?
June 2016 to August 2019

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
1. Miss Jennifer Petrie (public)
j.petrie@sheffield.ac.uk
2. Professor Solomon Tesfaye (scientific)
Solomon.Tesfaye@sth.nhs.uk

Trial website

http://www.sheffield.ac.uk/scharr/sections/dts/ctru/option-dm

Contact information

Type

Public

Primary contact

Miss Jennifer Petrie

ORCID ID

Contact details

Clinical Trials Research Unit
ScHARR
Regent Court
30 Regent Street
Sheffield
S1 4DA
United Kingdom
+44 114 222 0676
j.petrie@sheffield.ac.uk

Type

Scientific

Additional contact

Prof Solomon Tesfaye

ORCID ID

http://orcid.org/0000-0003-1190-1472

Contact details

Sheffield Teaching Hospitals and University of Sheffield
Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom
+44 114 271 2204
Solomon.Tesfaye@sth.nhs.uk

Additional identifiers

EudraCT number

2016-003146-89

ClinicalTrials.gov number

Protocol/serial number

STH18976

Study information

Scientific title

A multicentre, double-blind, centre-stratified multi-period crossover trial with a 6 month internal pilot to evaluate the efficacy of the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus

Acronym

OPTION-DM

Study hypothesis

Null hypothesis:
There is no difference between the study Treatment Pathways (amitriptyline supplemented with pregabalin, duloxetine supplemented with pregabalin and pregabalin supplemented with amitriptyline).

Alternative hypothesis:
There is a true difference between the study Treatment Pathways (amitriptyline supplemented with pregabalin, duloxetine supplemented with pregabalin and pregabalin supplemented with amitriptyline).

Ethics approval

Not provided at time of registration

Study design

Multicentre double-blind centre-stratified multiperiod crossover trial

Primary study design

Interventional

Secondary study design

Randomised cross over trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

Painful diabetic neuropathy

Intervention

All participants will receive all 3 treatment pathways. A web-based randomisation system will determine the order in which they receive the pathways. Participants will be allocated to one of 6 sequences in an equal allocation to sequences (1:1:1:1:1:1).

Treatment pathways:
1. Amitriptyline supplemented with pregabalin (if necessary)
2. Duloxetine supplemented with pregabalin (if necessary)
3. Pregabalin supplemented with amitriptyline (if necessary)

Each treatment pathway has 2 treatment periods: 6 weeks monotherapy followed by 10 weeks combination therapy. Those patients who have adequate pain relief after 6 weeks will remain on monotherapy for the second treatment period. Each treatment pathway is preceded by a one week washout period. Each treatment pathway will last around 4 months and participants will receive treatment within the trial for around one year.

There will be 3 dose levels for each drug. Participants will start on the lowest dose level of each drug and the dose will be titrated up to a maximum tolerated dose over the first 2 weeks of treatment.

Blinding will be maintained with over-encapsulated drugs and matching placebo. The participants and the local research team will be blinded to treatment allocation with the exception of the site pharmacist who will be unblinded.

Participants in all groups will be followed up after 6 and 16 weeks.

Subgroup analysis:
All participants will complete the Neuropathic Pain Symptom Inventory (NPSI) questionnaire, which is used to categorise patients for subgroup analysis relating pain phenotype to treatment response. In particular these outcomes will be evaluated:
1. Difference between “Burning (superficial) spontaneous pain” NPSI mean subscores - (evaluated at patient level) at week 16 among pathways
2. Difference between “Pressing (deep) spontaneous pain” NPSI mean subscores - (evaluated at patient level) at week 16 among pathways
3. Difference between “Paroxysmal pain” NPSI mean subscores - (evaluated at patient level) at week 16 among pathways
4. Difference between “Evoked pain” NPSI mean subscores - (evaluated at patient level) at week 16 among pathways
5. Difference between “Paresthesia/dysesthesia” NPSI mean subscores - (evaluated at patient level) at week 16 among pathways
6. Difference between NPSI mean total scores - (evaluated at patient level) at week 16 among pathways

Intervention type

Phase

Drug names

Primary outcome measures

Difference between 7 day average 24-hour pain evaluated at patient level using an 11 point NRS scale measured during the final follow-up week of each treatment pathway (Week 16)

Secondary outcome measures

Efficacy
1. Difference between 7-day average 24-hour pain (evaluated at patient level) on an 11 point NRS scale at Week 6 among monotherapies in each treatment pathway.
2. Health status is measured using RAND SF-36 physical mean scores at week 6 and 16 of each treatment pathway
3. Health status is measured using RAND SF-36 mental mean scores at week 6 and 16 of each treatment pathway
4. Proportion of patients having treatment success, defined as a reduction in 30% value at follow up compared to baseline, is measured by 7-day average 24-hour pain evaluated at patient level using an 11 point NRS scale at week 16 of each treatment pathway
5. Proportion of patients having treatment success, defined as a reduction in 50% value at follow up compared to baseline, is measured by 7-day average 24-hour pain evaluated at patient level using an 11 point NRS scale at week 16 of each treatment pathway
6. Pain interference with function total score is measured using the BPI-MSF at week 6 and 16 of each treatment pathway
7. Insomnia is measured using the Insomnia Severity Index at week 6 and 16 of each treatment pathway
8. Patient impression of change is measured using the Patient Global Impression of Improvement at week 16 of each treatment pathway
9. Care pathway preferred by participants is measured by patient interview at week 50

Cost Effectiveness
1. Cost Effectiveness is measured using the EuroQoL-5D-5L and a modified version of the Client Service Receipt Inventory (CSRI) at week 6 and week 16 of each treatment pathway

Safety
1. Proportion of patients reporting at least one Adverse Event for each of the pathway is measured by patient interview at each study visit or telephone call.
2. Frequencies of Adverse Events for each of the pathway is measured bypatient interview at each study visit or telephone call.
3. Listing of Adverse Events for each of the pathway is measured by patient interview at each study visit or telephone call.
4. Proportion of patients reporting at least one Serious Adverse Event for each of the pathway is measured by patient interview at each study visit or telephone call.
5. Frequencies of Serious Adverse Events for each of the pathway is measured by patient interview at each study visit or telephone call.
6. Listing of Serious Adverse Events for each of the pathway is measured by patient interview at each study visit or telephone call.

Subgroup
1. Relationship between pain phenotype and treatment response is measured using the Neuropathic Pain Symptom Inventory (NPSI) questionnaire at week 16 of each treatment pathway

Overall trial start date

01/06/2016

Overall trial end date

31/08/2019

Reason abandoned

Eligibility

Participant inclusion criteria

1. Aged 18 years and over
2. Daily pain for at least 3 months or taking pain medication for neuropathic pain for at least 3 months
3. Bilateral distal symmetrical polyneuropathy confirmed by Michigan Neuropathy Screening Instrument (MNSI) score > 3 at screening visit
4. Bilateral distal symmetrical polyneuropathy confirmed by the Douleur Neuropathique 4 (DN4) questionnaire at screening visit
5. Stable glycaemic control (HbA1c < 108mmol/mol)
6. Participants will have a mean total pain intensity of at least 4 on an 11-point numeric rating scale (NRS; with 0 being ‘no pain’ and 10 ‘worst pain imaginable’) during 1 week off pain medications (Baseline Period)
7. Willing and able to comply with all the study requirements and be available for the duration of the study. This will be a 1 year study in which all participants will undergo all Treatment Pathways regardless of treatment response and this point will be made clear
8. Willing to discontinue current neuropathic pain relieving medications
9. Informed consent form for trial participation signed by participant

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

392

Participant exclusion criteria

1. Non-diabetic neuropathies
2. History of alcohol/substance abuse
3. History of severe psychiatric illnesses
4. History of epilepsy
5. Contraindications to study medications
6. Pregnancy/breast feeding or planning pregnancy during the course of the study
7. Use of prohibited concomitant treatment (as detailed in section 8.10) that could not be discontinued
8. Use of high dose morphine equivalent (>120mg/day)
9. Liver disease (LFTs >2 times upper limit of normal)
10. Significant renal impairment (eGFR <30mL/minute/1.73m2)
11. Heart failure New York Heart Association (NYHA) ≥ class II
12. Clinically significant cardiac arrhythmias on 12 lead ECG
13. Prior history of ischaemic heart disease
14. Postural hypotension (reduction of > 20mmHg)
15. Prostatic hypertrophy or urinary retention
16. Any suicide risk as judged by the investigator or as defined by a score of ≥2 on the suicide risk questionnaire
17. Significant language barriers which are likely to affect the participant's understanding of the medication schedule or ability to complete outcome questionnaires

Recruitment start date

01/03/2017

Recruitment end date

28/02/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Sheffield Teaching Hospitals NHS Foundation Trust
Royal Hallamshire Hospital Glossop Road
Sheffield
S10 2JF
United Kingdom

Trial participating centre

Oxford University Hospitals NHS Foundation Trust
Headley Way
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Nottingham University Hospitals NHS Trust
Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

Poole Hospital NHS Foundation Trust
Longfleet Road
Poole
BH15 2JB
United Kingdom

Trial participating centre

Tameside Hospital NHS Foundation Trust
Fountain Street
Ashton-under-Lyne
OL6 9RW
United Kingdom

Trial participating centre

Ipswich Hospital NHS Trust
Heath Road
Ipswich
IP4 5PD
United Kingdom

Trial participating centre

Kings College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

Lancashire Teaching Hospitals NHS Foundation Trust
Sharoe Green Lane North Fulwood
Preston
PR2 9HT
United Kingdom

Sponsor information

Organisation

Sheffield Teaching Hospitals NHS Foundation Trust

Sponsor details

Clinical Research Office
D Floor
Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal, in late 2019/early 2020.

Intention to publish date

31/03/2020

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes