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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) -

SLCTR Registration Number

SLCTR/2018/033


Date of Registration

19 Oct 2018

The date of last modification

Nov 05, 2018



Application Summary


Scientific Title of 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)


Public Title of 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)


Disease of Health Condition(s) Studied

Paroxysmal Nocturnal Haemoglobinuria (PNH)


Scientific Acronym

CAPSTONE


Public Acronym

CAPSTONE


Brief title

rVA576 for the treatment of PNH


Universal Trial Number

NA


Any other number(s) assigned to the trial and issuing authority

Trial Details Registered with www.clinicaltrialsregister.eu EudraCT Number: 2017-003847-39 Registered with clinicatrials.gov Clinicaltrials.gov number: NCT03588026


Trial Details


What is the research question being addressed?

Comparison of the efficacy of rVA576 versus standard of care for patients with uncontrolled haemolysis due to paroxysmal nocturnal haemoglobinuria (PNH). Standard of care is defined as packed red blood cells (PRBC)


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Masking not used


Control

Standard therapy


Assignment

Parallel


Purpose

Treatment


Purpose

Phase 3


Intervention(s) planned

Study sites • Colombo North Teaching Hospital, Ragama • Colombo South Teaching Hospital, Kalubowila • Jaffna Teaching Hospital, Jaffna • National Hospital of Sri Lanka

CAPSTONE is a three-part, two-arm randomised, controlled (standard of care), parallel group study. The trial will run in 3 parts as below:

Screening Period: Up to 21 days where patients will be assessed in order to confirm they meet all Inclusion criteria and do not to meet any of the Exclusion criteria.

Part 1– Observation Period: A 3-month observation period in which patients will be treated with Standard of Care (SoC). During Part 1, the following 2 events may occur: • Patients receive a qualifying transfusion that permits entry into Part 2 of the trial • Patients who do not require a qualifying transfusion by the end of the observation period will leave the trial (withdrawn patients) and will not be permitted to be rescreened. Patients who receive a qualifying transfusion will have the haemoglobin (Hb) value which triggered the requirement for a transfusion used as their set point which mandates the Hb level at which further transfusions will take place in Part 2 (see below). Patients should receive their qualifying transfusion based on the algorithm within a maximum of 48 hours of the Hb value which triggered the clinical decision to transfuse.

Part 2: A 6-month treatment period where patients will be randomised 1:1 to either rVA576 plus SoC (Arm 1) or SoC (Arm 2). Following receipt of the qualifying transfusion in Part 1, patients should move into Part 2 within 1- 3 days to begin treatment under Part 2. The ablating dose cannot be given the same day as the qualifying transfusion, since patients should receive the ablating dose at a suitable time in the morning. Patients in Part 2 who fall below their Hb set point will receive an appropriate number of units of packed red blood cells (PRBCs) according to a pre-determined algorithm based on prior transfusion history. The Hb value which triggered the requirement for the qualifying transfusion in Part 1 will be used as their set point.

Part 3: A 3-month maintenance period at the end of Part 2 after 6 months of treatment, all patients will move to Part 3 for 3 months: the patients in Arm 1 (rVA576 plus SoC) will continue receiving treatment for a further 3 months. The patients in Arm 2 (SoC) will switch from SoC only to rVA576 plus SoC for 3 months. At the end of Part 3 all patients will be offered the chance of continuing to receive rVA576 under the long-term Safety study AK581 (CONSERVE) if the Investigator believes the patient is benefitting from treatment. This study will randomise 1:1 a minimum of 30 patients into Part 2 of the study (approximately 15 to receive rVA576 plus SoC, and approximately 15 to continue with their SoC). Randomisation will be stratified based on the number of transfusions of whole blood or packed red blood cells (PRBC) received within the 12 months prior to entering the observation period (low stratum: 4-14 units, high stratum: ? 15 units). For each arm starting treatment with rVA576, the patient will receive an ablation dose (AD) of 60 mg followed by one dose of 30 mg 12 hours later (this will be considered Day 1 for rVA576 treatment). The patient will then continue with a dose of 22.5 mg every 12 hours administered for Days 2 – 28 (± 3days), during which the patient is stabilised on treatment with rVA576. At Day 29, the patient will move to a dose of 45mg once daily up to Day 270 in Arm 1 and up to Day 90 in Arm 2. rVA576 will be administered subcutaneously.


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


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 109/L OR (b) neutrophils < 0.5 x 109/L
  3. Patients with a platelet count of ? 70 x 109/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 Presence or suspicion of active bacterial infection requiring antibiotic therapy in the opinion of the Investigator.


Primary outcome(s)

• Haemoglobin stabilisation rate defined as haemoglobin greater than the set point for each patient defined during the pre-study randomisation period. • The avoidance of PRBC transfusions during the treatment period


Primary outcome(s) - Time of assessment(s)

The primary endpoint will be assessed at the end of Part 2 - day 180


Secondary outcome

  1. Number of units of PRBC transfused from baseline Day 1 (start of Part 2) to Day 180
  2. Percentage of patients who achieve transfusion avoidance from baseline Day 1(start of Part 2) to Day 180
  3. Change in QoL score using FACIT-F from baseline Day 1 (start of Part 2) to Day 180
  4. AUC [LDH] from baseline Day 1 (start of Part 2) to Day 180
  5. CH50 levels from baseline Day 1 (start of Part 2) to Day 180

Secondary outcome(s) - Time of assessment(s)

Each outcome will be assessed at Day 180



Target number/sample size

Globally-30 subjects From Sri Lanka- Approximately 10 subjects


Countries of recruitment

Kazakhstan, Lithuania, Peru, Romania, Sri Lanka


Anticipated start date

2018-10-19


Anticipated end date

2020-07-22


Recruitment status

Pending


State of ethics review approval

Approved by Ethics Review Committee, Faculty of Medicine, University of Kelaniya on 10 July 2018 under the reference number P/118/05/2018


Funding source

Akari Therapeutics Plc, United Kingdom



Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Dr Senani Williams
Consultant Haematologist
Department of Pathology, Faculty of Medicine, University of Kelaniya
Tel: +94 2961000 Ext 192
Mob: +94 77 9548740

senaniw@kln.ac.lk

Contact Person for Public Queries

Dr Senani Williams
Consultant Haematologist
Department of Pathology Faculty of Medicine University of Kelaniya
Tel: +94 2961000 Ext 192
Mob: +94 77 9548740

senaniw@kln.ac.lk


Primary study sponsor/organization

Wynne Weston-Davies

75-76 Wimpole Street London, W1G 9RT United Kingdom
Tel: +44(0)2080040268

wynne.weston-davies@akaritx.com

Secondary study sponsor (If any)