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    Summary
    EudraCT Number:2017-003847-39
    Sponsor's Protocol Code Number:AK580
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-01-23
    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 ConcernedLithuania - SMCA
    A.2EudraCT number2017-003847-39
    A.3Full title of the trial
    CAPSTONE: Phase III Confirmatory Assessment Protocol: rVA576 Safety and Efficacy in Three-Part, Two-Arm, Randomised Open Label Evaluation in patients with Paroxysmal Nocturnal Haemoglobinuria (PNH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the safety and efficacy of rVA576 in patients with Paroxysmal Nocturnal Haemoglobinuria (PNH)
    A.3.2Name or abbreviated title of the trial where available
    CAPSTONE
    A.4.1Sponsor's protocol code numberAK580
    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 SponsorAkari Therapeutics Plc.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAkari Therapeutics Plc.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAkari Therapeutics Plc.
    B.5.2Functional name of contact pointWynne Weston-Davies
    B.5.3 Address:
    B.5.3.1Street Address75-76 Wimpole Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW1G 9RT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44(0)2080040268
    B.5.6E-mailwynne.weston-davies@akaritx.com
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1725
    D.3 Description of the IMP
    D.3.2Product code rVA576
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNA
    D.3.9.2Current sponsor coderVA576
    D.3.9.4EV Substance CodeSUB182098
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number18
    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 No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Paroxysmal Nocturnal Haemoglobinuria (PNH)
    E.1.1.1Medical condition in easily understood language
    acquired genetic haemolytic anaemia
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10034042
    E.1.2Term Paroxysmal nocturnal haemoglobinuria
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of rVA576 plus SoC compared to SoC in patients with uncontrolled haemolysis due to paroxysmal nocturnal haemoglobinuria (PNH).
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of rVA576 in treatment of patients with PNH.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing to give informed consent to treatment with rVA576
    2. Diagnosed with paroxysmal nocturnal haemoglobinuria (PNH) confirmed by flow cytometry
    3. Have not received any complement inhibitor within the 4 months prior to screening
    4. ≥ 18 years of age at the time of screening
    5. Weight ≥50kg
    6. Complete transfusion medical history for 12 months prior to entering the observation period and definitely prior to receiving the qualifying transfusion must be available to the patient's investigator and be verifiable by the Sponsor or its representative.
    7. Transfusion dependent and has received at least 4 episodes of transfusion of whole blood or PRBC during the 12 months prior to entering the observation period (Part 1), with a minimum of 4 units in total, and a minimum of 1unit at each transfusion episode.
    8. LDH ≥1.5 x the ULN per the local lab.
    9. Willing to receive appropriate prophylaxis against Neisseria meningitidis infection by both immunisation and continuous or intermittent antibiotics.
    10. Willing to avoid prohibited medications such as other complement inhibitors and chemotherapeutic agents
    11. Patients must agree to avoid pregnancy and fathering children from the time of signing the Informed Consent Form until 90 days after the last dose of rVA576. Permitted contraceptive methods that are ≥99% effective in preventing pregnancy should be communicated to trial patients and their understanding confirmed. Two approved methods of highly effective contraception must be used by the patient and their partner.
    12. Patients who are on erythropoietin and/or immunosuppressant treatment should be on stable doses for at least 6 months prior to entering the observation period (Part 1). The dose of these drugs should not be changed during Part 1 or 2.
    13. Patients who are taking systemic corticosteroids should be on a stable dose for at least 4 weeks prior entering the observation period (Part 1). If corticosteroids, either topical or systemic, are being taken for reasons unconnected with the target condition (e.g. for allergic rhino-conjunctivitis) they may be adjusted as clinically appropriate but otherwise should remain at constant dosage.
    14. Patients on anticoagulant therapy should be well-controlled prior to entry into the observation period (Part 1) and control should be maintained as long as anticoagulation is considered to be an appropriate therapy. A change of up to 20% to a previously stable anticoagulant therapy is permitted
    15. Patients taking iron and/or folic acid supplements should be on a stable dose for at least 4 weeks prior to entering the observation period (Part 1). The dose of iron and/or folic acid supplements should not be adjusted during the trial.

    PART 2 Inclusion Criteria
    1. Complete transfusion medical history for 12 months prior to receiving qualifying transfusion must be available to the patient's investigator and be verifiable by the Sponsor or its representative.
    2. A qualifying transfusion is mandatory during Part 1 with Hb≤70g/L (7g/dL) with or without symptoms or >70g/L (7g/dL) to ≤90g/L (9g/dL) with symptoms.
    3. The qualifying transfusion during the observation period (Part 1) requiring a minimum of 1 unit of PRBC. The quantity of PRBC to be transfused will be according to the algorithm in the protocol.
    4. Patient must be within 15g/L (1.5g/dL) of the mean haemoglobin from the previous 12 months
    5. Will have a minimum of 1 sign or 1 symptom of PNH from the following list: frank haemoglobinuria, dysphagia, dyspnoea, abdominal pain, erectile dysfunction, evidence of recent thrombotic event, or excessive fatigue, which leads to the qualifying transfusion.
    6. A negative nasal and throat swab result for N. meningitidis in the last assessment.
    7. Patient must be available to enter Part 2 within 3 days of receiving a qualifying transfusion in Part 1.
    8. Continues to meet all the inclusion criteria and none of the exclusion criteria.

    E.4Principal exclusion criteria
    1. Patients whose mean haemoglobin level over the previous 12 months prior to screening was greater than 105 g/L (10.5g/dL).
    2. Severe bone marrow failure as manifested by (a) a peripheral blood reticulocyte count <20 x 10exp9/L OR (b) neutrophils < 0.5 x 10exp9/L
    3. Patients with a platelet count of ≤ 70 x 10exp9/L
    4. Patients with known or suspected acquired somatic mutations affecting the bone marrow (e.g. acute myeloid leukaemia) which may be associated with PNH.
    5. Chemotherapy within 3 months of screening visit.
    6. History of recurrent bacterial infections or suspicion of active bacterial infections requiring antibiotic therapy.
    7. Planned or actual pregnancy or breast feeding (females).
    8. Known allergy to ticks or severe reaction to arthropod venom (e.g. bee or wasp venom).
    9. Unresolved N. meningitidis infection. Patients who have positive nasal or throat swabs must be excluded until eradication of the organism by antibiotic treatment has been confirmed by repeat swabbing and growth testing.
    10. Patients who are not willing to receive adequate immunisation against N. meningitidis unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of developing a meningococcal infection.
    11. Impaired hepatic function (bilirubin > 1.5 x ULN and AST/ALT >2.5 x ULN) unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of treatment in the presence of impaired hepatic function.
    12. Patients with a glomerular filtration rate (GFR) of <30mL/min/1.73m2 unless, in the opinion of the investigator, the risks of delaying therapy outweigh the risks of treatment in the presence of impaired renal function.
    13. Participation in other clinical trials within 4 weeks of signing the consent form.
    14. History of active systemic autoimmune diseases other than the target condition. Dermatologic diseases such as psoriasis will not be a reason for exclusion unless there are associated systemic symptoms such as psoriatic arthritis.
    15. Any other systemic disorders that could interfere with the evaluation of the study treatment.
    16. Failure to comply with protocol requirements
    17. Known Hepatitis B or Hepatitis C, as per medical history.

    PART 2 Exclusion Criteria
    1. Presence or suspicion of active bacterial infection requiring antibiotic therapy in the opinion of the Investigator.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is haemoglobin stabilisation rate defined as haemoglobin greater than the set point for each patient defined during the pre-study randomisation period, and the avoidance of PRBC transfusions during the treatment period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be assessed at the end of Part 2.
    E.5.2Secondary end point(s)
    •Number of units of PRBC transfused from baseline Day 1 (start of Part 2) to Day 180
    •Percentage of patients who achieve transfusion avoidance from baseline Day 1(start of Part 2) to Day 180
    •Change in QoL score using FACIT-F from baseline Day 1 (start of Part 2) to Day 180
    •AUC [LDH] from baseline Day 1 (start of Part 2) to Day 180
    •CH50 levels from baseline Day 1 (start of Part 2) to Day 180
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 180
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Ecuador
    Kazakhstan
    Peru
    Sri Lanka
    Turkey
    Lithuania
    Romania
    E.8.7Trial has a data monitoring committee No
    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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 30
    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)
    After treatment period with rVA576, the patients may enter the long-term safety trial provided they are benefiting from treatment and the Investigator feels this would be in the patient’s best interest. The decision to continue on rVA576 should be made by the patient in consultation with the PI at /or about Day 150 time-point for those patients in Arm1 and at /or about Day 269 time-point for subjects in Arm 2.

    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-03-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-09-03
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