YQ23 Study in Patients With Critical Limb Ischaemia

This is an early phase study to assess how safe and tolerable is the new study drug YQ23 and to compare the effectiveness of YQ23 against normal saline to treat critical limb ischaemia. The study also aims to understand how it affects the body and an optional substudy to assess how the human body takes up, breaks down, and clears the study drug.

Eligible patients will be randomised to have a 2:1 chance to receive a single, intravenous, fixed dose of YQ23 or normal saline. Neither the patient nor the study site will know which treatment has been given.

On the day of YQ23 administration, patients will be asked to stay in the study site for 3 days for safety observation. After discharge, they will be required to visit the study clinic for 3 times in a year to continue safety monitoring and assessment of treatment effect.

Each subject's participation will be about 13 months after signing the informed consent.

This is a Phase 1b/2a, randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of an investigational product, YQ23, in patients with Critical Limb Ischaemia (CLI) during a follow-up period of 12 months.

Fifty-one patients are planned for enrolment. The study consists of a screening period (up to 28 days), a double-blind treatment period, and a follow-up (12 months). Prior to randomisation, patients diagnosed with CLI will be stratified into:

* Group of patients in whom revascularisation is not planned
* Group of patients with planned revascularisation

Within each group, patients will be randomised in a 2:1 ratio to receive single intravenous infusion of YQ23 120 mg/kg and normal saline, respectively at the study site.

On the day of YQ23 administration, the patient will be admitted to the study site on Day 1 and will be discharged on Day 3. The total duration of participation in the study for each patient is approximately 13 months. Data on the study endpoints will be collected from baseline (pre-dose on Day 1), Day 3, Month 1, 6 and up to 12 months after study treatment infusion.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of CLI (Rutherford Classification stage 4, 5 or 6) including at least one of the following:

  1. resting ankle systolic pressure (either dorsalis pedis or posterior tibial artery) \<=70 mmHg in affected limb
  2. resting toe systolic pressure \<=50 mmHg in affected limb
  3. TcPO2 \<=30 mmHg
* One of the following clinical presentations:

  1. pain at rest
  2. ischaemic ulcer, and/or focal gangrene for at least 2 weeks
* Diagnosis of severe lower extremity peripheral artery occlusive disease as evidenced by either:

  1. Documented significant stenosis (\>=75%) of \>=1 of the following arteries: superficial femoral, popliteal, and infra-popliteal arteries, as assessed by imaging test, or
  2. ABI \<=0.80 or TBI \<=0.60 of the index leg (in the event of non-compressible ankle arteries) for patients without a prior history of limb revascularization on the index leg, or an ABI \<=0.85 or TBI \<=0.65 of the index leg (in the event of non-compressible ankle arteries) for patients with a prior history of limb revascularization on the index leg.
* Contraceptive use

  1. Male patients and their female spouses/partners who are of childbearing potential must agree to use a high effective contraception consisting of two forms of birth control detailed in the protocol during the treatment period and for at least 6 days after the dose of the study treatment and refrain from donating sperm during this period
  2. A female patient is eligible if she is not pregnant, not breastfeeding, and at least on of the following conditions applies: (i) not a woman of childbearing potential (WOCBP), (ii) A WOCBP who agrees to follow the contraceptive guidance in the protocol during the treatment period and for at least 6 days after the dose of study treatment and refrain from donating ova during this period
* Patient is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent and the protocol

Exclusion Criteria:

* Patients who have undergone successful revascularisation on the index leg within 4 weeks of the qualifying event
* Patients with estimated life expectancy \<12 months
* Acute limb ischaemia due to thromboembolism within 2 weeks of the qualifying event
* Recent myocardial infarction within 30 calendar days prior to signing informed consent
* Recent stroke within 30 calendar days prior to signing informed consent
* Known history of severe congestive heart failure as determined through review of medical history
* Haemoglobin \<8 g/dL, albumin \<3 g/dL or other clinically significant abnormalities in the laboratory tests at screening
* Unwilling to complete follow-up evaluation
* Uncontrolled arterial hypertension with systolic blood pressure (SBP) \>180 mmHg and/or diastolic blood pressure (DBP) \>100 mmHg at screening
* Patients with history of long QT syndrome or whose QTc (calculated according to Bazett formula QTc = QT/ √RR) \>470 ms at screening
* Patients with severe left ventricular dysfunction of \<40% at screening
* Patients with clinically significant abnormalities in ECG parameters (other than QTc) or in the physical examination at screening that might comprise patient safety
* History of coagulopathy
* Patients having significant renal impairment with estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m2 as determined by the 4-variable Modification of Diet in Renal Disease (MDRD) equation at Screening, except those patients who are on continuous ambulatory peritoneal dialysis(CAPD) or hemodialysis (HD)
* Significant liver impairment (abnormal Liver Function Tests \>3 x upper limit of normal)
* Patients with active Hepatitis B infection (HBsAg positive and HBeAg positive) at screening
* Patient with a positive test for Hepatitis C virus antibody (anti-HCV) at screening
* Patient with known history of infection with human immunodeficiency virus (HIV) or any other active or chronic infection
* Patients with evidence of uncontrolled hypo- or hyperthyroidism
* History active malignancy (as determined through review of medical history), excluding local skin cancer (basal or squamous cell carcinoma)
* Patients unable to provide informed consent
* Known allergy to bovine products
* Receipt of bovine haemoglobin-based oxygen carrier (HBOC) or other HBOC in the past
* Use of an investigational drug or treatment within 12 months prior to signing informed consent; concurrent participation in any other investigational protocol
* Pregnancy and breastfeeding, as well as unwillingness to use effective methods contraception for women of childbearing potential