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    Summary
    EudraCT Number:2012-000058-73
    Sponsor's Protocol Code Number:LIPS
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-08-03
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2012-000058-73
    A.3Full title of the trial
    A multi-centre (UK) double-blind randomised parallel group placebo controlled trial to evaluate the efficacy, safety, and tolerability of Intravenous Immunoglobulin (IVIg) 0.5g/kg plus standard treatment, versus matched placebo plus standard treatment in patients with longstanding Complex Regional Pain Syndrome.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Low-dose Intravenous Immunoglobulin Treatment for Complex Regional Pain Syndrome (LIPS Trials)
    A.3.2Name or abbreviated title of the trial where available
    Low-dose Intravenous Immunoglobulin Treatment for CRPS (LIPS Trial)
    A.4.1Sponsor's protocol code numberLIPS
    A.5.4Other Identifiers
    Name:University of LiverpoolNumber:UOL000773
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Liverpool
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBiotest UK Ltd
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportPain Relief Foundation
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportNIHR EME
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKing's College London
    B.5.2Functional name of contact pointCaroline Murphy
    B.5.3 Address:
    B.5.3.1Street AddressKing's Clinical Trials Unit, IoP, KCL
    B.5.3.2Town/ city16 De Crespigny Park, London
    B.5.3.3Post codeSE5 8AF
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02078480532
    B.5.6E-mailcaroline.murphy@kcl.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorWalton Centre NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Intratect
    D.2.1.1.2Name of the Marketing Authorisation holderBiotest Pharma GmbH, Landsteinerstrasse 5, D-63303 Dreieich, Germany
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameHuman normal immunoglobulin for intravenous use (IVIg)
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman normal immunoglobulin for intravenous use (IVIg)
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit g/l gram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Complex Regional Pain Syndrome
    E.1.1.1Medical condition in easily understood language
    Chronic pain condition, usually affecting a limb, which develops after a minor injury
    E.1.1.2Therapeutic area Body processes [G] - Bones and nerves physological processes [G11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10049475
    E.1.2Term Chronic pain
    E.1.2System Organ Class 100000004867
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To gain, within 44 months, both definite proof of the clinical efficacy, and a more confident estimate of the effect size of low-dose IVIg treatment to reduce pain in patients with msCRPS.
    E.2.2Secondary objectives of the trial
    To achieve better understanding of this technology, including:
    1. effect stability with repeat administration
    2. factors predicting a beneficial response
    3. effects on additional outcome parameters including stimulus evoked pain, pain interference, quality of life, and short-term risk profile
    4. Health economics evaluation
    5. to create a resource of biological samples at the University of Liverpool for future CRPS serum autoantibody, and serum-substances research
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of Complex Regional Pain Syndrome I or II according to Budapest research criteria (appendix 5) (22).
    2. Disease duration of 1-5 years and a mean pain intensity on an 11-point (0-10) Numeric Rating Scale (NRS) over the first seven daily entries after screening within a pre-defined range (see section 9 for details of pain thresholds for eligibility)
    3. Failure to respond (poor efficacy or unacceptable side effects) to drugs recommended for the treatment of neuropathic pain (23), including pregabalin or gabapentin, a tricyclic antidepressant, and mild and strong opioids (where not contraindicated or refused by the patient).
    4. Previous specialised pain physiotherapy (24), including desensitisation techniques, and either mirror therapy (25) or graded motor imagery treatment (26), or both (where not contraindicated or refused by the patient).
    5. Willingness to confirm the use of adequate birth control while on the trial will be required in pre menopausal women without evidence for an inability to become pregnant.
    6. Willingness to not start any other treatment for during the parallel part of the trial
    7. Age 18 years and above
    E.4Principal exclusion criteria
    Any individuals meeting any of the following will be excluded from the study:
    1. Other significant chronic pains, which in the view of the study doctor may make assessment of the pain arising from CRPS difficult,
    2. If the patient recently started a new therapy for CRPS, which in the view of the study doctor may change the patient’s pain level during the time of participation in the trial.
    3. Unstable medical conditions
    4. Litigation. Patients in litigation will be excluded only if conclusion of that litigation is imminent during the course of the study.
    5. Pregnant or breastfeeding patients.
    6. Complete IgA deficiency
    7. Rare contraindications to IVIg therapy as per summary of product characteristics (SmPC)
    8. Receiving IVIg for other reasons,
    9. Patients previously enrolled in CRPS IVIg/SCIG trials
    10. Drugs or alcohol abuse
    11. Psychiatric or mental health disorder which could in the judgement of the site investigator interfere with successful study participation
    12. Unwillingness or inability to complete daily diaries, or inability to understand the questionnaires being used.
    13. Cancer other than basal cell carcinoma within the last 5 years. However those patients who have received definitive treatment, such as curative surgery more than 6 months ago, with no known recurrence can be included.
    14. A history of hypercoagulable or thrombophilic clotting abnormalities.
    15. A history of thrombembolic events: ischaemic stroke, confirmed myocardial infarction, pulmonary embolism; deep venous thrombosis except where immobility related (e.g. after injury or operation).
    16. Unstable angina.
    17. Renal failure, or serum creatinine greater than 1.5 times the upper limit of normal at screening.
    18. Any medical condition which in the opinion of the investigator would make it unsafe for the patient to participate or which would interfere with assessment of the outcome measures.
    19. Participation in another interventional trial within 3 months of randomisation. Participation in non-interventional studies is not a reason for exclusion.
    E.5 End points
    E.5.1Primary end point(s)
    • The primary outcome is the average 24h pain intensity over 37 days, recorded in pain diary entries for the previous 24 hours collected on days 6 to 42 (day 1=day of first infusion). Consenting patients providing a mobile phone number will be prompted automatically by SMS daily from day 2-42 to enter their pain intensity into their diary. In addition return SMSs from the patient, with the daily NRS pain value will be automatically saved as backup for the paper diary. The paper diary score will override the texted diary score, however every effort will be made to resolve any discrepancies. In participating patients unexplained lack of a response over two or three days will prompt a phone call from the study nurse to confirm that there are no issues.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Diary data collected daily from day 6 to day 42 post randomisation
    E.5.2Secondary end point(s)
    • Secondary outcomes will be pain interference measured using the interference subscale of the Brief Pain Inventory(11)1,and quality of life measured using the Euroqol EQ-5D-5L(12).

    • All other outcomes are exploratory.

    List of measures to be used:
    • Screening pain diaries (average 24h pain intensity numeric rating scale (NRS) only)
    • Detailed daily (three items: pain unpleasantness(13), average 24h NRS pain intensity, last 24h sleep quality (14))-and simplified weekly (weekly NRS pain intensity) pain diaries
    • Adverse events
    • Brief Pain Inventory- (diagram, worst pain intensity, and interference scales only) (11)
    • Concomitant medications
    • Concomitant therapies
    • Patient weight
    • Skin temperature measured with a surface thermometer
    • Limb volume measured with a water-bath technique
    • EQ-5D (5 Item)(12)
    • Expectations from treatment (15)
    • Functional items and fatigue suggested by-, and developed together with patient group (5 scales)
    • Patient Global Impression of change (16)
    • Hospital Anxiety and Depression Scale (17)
    • Health and Social care utilisation
    • Limb Exam recording Budapest CRPS signs, and any additional abnormalities on inspection, and sensory (cotton wool, pinprick, cold-fork) and motor (observation of active range) examination
    • McGill(18)
    • Quantitative Sensory Testing in 40 patients with stimulus evoked pain, excepting thermosensitivities (only in three trial centres)
    • Sullivan’s Pain Catastrophising Scale (19)
    • Time trade-off (20)
    • Work interference (Stanford Presenteeism Scale) (21)

    E.5.2.1Timepoint(s) of evaluation of this end point
    Weekly or daily diary data collected up to day 148.

    Major data collection timepoints at days 22 and 43 post-randomisation
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days29
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days29
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 108
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state108
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 108
    F.4.2.2In the whole clinical trial 108
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There is no arrangement to continue the treatment beyond the end of the trial. All patients will be offered up to two open label infusions of IVIg after they have completed the double blind phase of the trial, should they wish to receive them. Any treatment beyond this would be the decision of the treating clinician as this is not a licensed indication for this treatment.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-03-19
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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