A study to assess the safety and efficacy of rVA576 in patients with Paroxysmal Nocturnal Haemoglobinuria (PNH)

• Register: EUCTR
• Last refreshed on: 26 April 2021
• Main ID: EUCTR2017-003847-39-LT
• Date of registration: 23/01/2018
• Prospective Registration: Yes
• Primary sponsor: Akari Therapeutics Plc.
• Public title: A study to assess the safety and efficacy of rVA576 in patients with Paroxysmal Nocturnal Haemoglobinuria (PNH)
• Scientific title: 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) - CAPSTONE
• Date of first enrolment: 12/03/2018
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003847-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Ecuador, Kazakhstan, Lithuania, Peru, Romania, Sri Lanka, Turkey

Contacts

• Name: Wynne Weston-Davies
• Affiliation: Akari Therapeutics Plc.

• Name: Wynne Weston-Davies
• Affiliation: Akari Therapeutics Plc.

Key inclusion & exclusion criteria

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: fra
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.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Paroxysmal Nocturnal Haemoglobinuria (PNH)
MedDRA version: 21.1 Level: PT Classification code 10034042 Term: Paroxysmal nocturnal haemoglobinuria System Organ Class: 10038359 - Renal and urinary disorders

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Code: rVA576
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: NA
Current Sponsor code: rVA576
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 18-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: The primary endpoint will be assessed at the end of Part 2.

Primary 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.

Secondary Objective: To assess the safety and tolerability of rVA576 in treatment of patients with PNH.

Main Objective: To demonstrate the efficacy of rVA576 plus SoC compared to SoC in patients with uncontrolled haemolysis due to paroxysmal nocturnal haemoglobinuria (PNH).

Secondary Outcome(s)

Secondary 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

Timepoint(s) of evaluation of this end point: Day 180

Secondary ID(s)

AK580

Source(s) of Monetary Support

Akari Therapeutics Plc.

Ethics review

Status: Approved
Approval date: 05/03/2018
Contact: