Assessing the Safety and Ability of SG1002 to Overcome Deficits in Hydrogen Sulfide in Heart Failure Patients

A Dose Escalation Study to Assess the Safety and Ability of SG1002 to Overcome Circulating Deficits in Hydrogen Sulfide Found in Heart Failure Patients

Patients with heart failure are reported to have lower levels of hydrogen sulfide in their blood, even though sulfur is available naturally in the diet. Hydrogen sulfide is a molecule that has been shown to have a number of beneficial effects and thus the low levels may contribute to the disease. This trial is testing whether a medical food product of synthetic sulfur molecules, SG1002, can overcome this deficit in blood levels of hydrogen sulfide.

Subjects with heart failure have been shown to have a deficit in circulating hydrogen sulfide levels, which, since sulfur is not readily bioavailable and is declining in food substances, cannot be treated adequately by diet alone. This deficit in circulating hydrogen sulfide is thought to lead to increases in oxidative stress and with this, associated problems that can contribute to heart failure. This is a study to evaluate the safety and ability of multiple doses of oral SG1002 in subjects with heart failure to reverse the deficits in circulating hydrogen sulfide. The primary objective is to assess the safety and the ability of multiple doses of twice daily administration of SG1002 compared with placebo to increase circulating levels of hydrogen sulfide. Initially, a dose escalation study will be carried out for 21 days in 4 normal subjects, randomized 3:1 active:placebo. Subjects will receive a 200 mg dose BID for 7 days and in no adverse events, escalate to 400 mg for 7 days then 800 mg for 7 days. Safety parameters will be assessed for each dose, along with pharmacokinetic analysis and markers of oxidative stress and heart failure. Following completion of the normal healthy subjects, 10 heart failure subjects will be randomized 4:1 active:placebo and tested as described above.

Inclusion Criteria (healthy volunteers):

• Healthy male volunteers aged between 18 and 45 years (inclusive);
• Body mass index between 19 and 30 kg/m^2 (inclusive);
• No clinically significant findings in the medical history and physical examination;
• No clinically significant laboratory values and urinalysis, unless the investigator considers any abnormality to be clinically irrelevant;
• Normal ECG, blood pressure and heart rate, unless the Investigator considers any abnormality to be not clinically significant (NCS);
• Willing to use contraception (single barrier methods); and
• Willing and able to provide written informed consent.

Exclusion Criteria (healthy volunteers):

• Have received blood products within 1 month prior to Screening;
• Have received any investigational research agent within 30 days or 5 half-lives (whichever is longer) prior to the first dose of trial medical food;
• Have received an investigational vaccine within 6 months, a live attenuated vaccine within 60 days or a registered vaccine within 30 days prior to the first dose of the trial medical food;
• Have a history of thyroidectomy or thyroid disease that required medication within the past 12 months;
• Have had serious angioedema episodes within the previous 3 years or requiring medication in the previous two years;
• Have a bleeding disorder diagnosed by a doctor (for example factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties during blood draws;
• Have a psychiatric condition that precludes compliance with the protocol, past or present psychoses, past or present bipolar disorder, or a disorder requiring lithium, within five years prior to enrolment;
• Has a history of suicide plan;
• Any clinically significant abnormality at Screening determined by medical history, physical examination, blood chemistry, haematology, urinalysis and a 12-lead ECG, or positive urine screen for drugs of abuse;
• Any other condition which in the view of the Investigator is likely to interfere with the study or put the subject at risk;
• HIV, or hepatitis B or C positive;
• Have a history of or current clinically significant gastrointestinal, hepatic, renal, cardiovascular, respiratory, endocrine, oncological, immunodeficiency, neurological, metabolic, haematological or autoimmune disorder;
• Have a history of or current tuberculosis, epilepsy, diabetes or glaucoma;
• Have clinical signs of active infection or a temperature more than 38.0°C at the time of screening. Study entry may be deferred at the discretion of the Principal Investigator;
• Have evidence of drug or alcohol abuse;
• Be unable to provide repeated blood samples without undue trauma or distress;
• Anticipate surgery within the trial period; or
• Inability to speak English (due to need to administer standardized English-language questionnaire).

Inclusion Criteria (heart failure subjects):

• Aged between 35 and 85 years (inclusive);
• Has symptomatic heart failure, with New York Heart Association (NYHA)classification of II or III;
• Ambulatory;
• Left ventricular ejection fraction less than 40%;
• Congestive heart failure has been stable for the previous 3 months (defined by no change in baseline therapy or symptoms of heart failure for the previous 3 months); and
• Willing and able to provide written informed consent.

Exclusion Criteria (heart failure subjects):

• Subject is pregnant or breastfeeding;
• If female, the subject is either post-menopausal or surgically sterilised or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) from signing of the informed consent form though to the Final Visit/Early Termination Visit;
• Myocardial infarction, unstable angina, stroke, cerebrovascular accident, percutaneous coronary intervention, open heart surgery or transient ischemic attack (TIA) within 3 months prior to Screening;
• Current symptomatic hypotension (defined as systolic blood pressure (SBP) ≤ 90 mmHg or diastolic blood pressure (DBP) ≤ 40 mmHg);
• Poorly controlled hypertension (defined as SBP ≥ 160 mmHg or DBP ≥ 100 mmHg) despite therapy
• Subjects with NYHA grade IV heart failure;
• Subjects awaiting percutaneous coronary intervention or open heart surgery;
• Subjects with serious liver disease;
• Subjects with liver function test results three times the upper limit of normal.
• Any change in cardiovascular drug therapy within three months prior to randomization
• History of chronic obstructive pulmonary disease (diagnosed using GOLD criteria) or evidence of restrictive lung disease (defined as forced expiratory volume (FEV1) to forced vital capacity (FCV) ratio of > 80%);
• Poorly controlled diabetes (defined as HbA1c > 10.0 %);
• Has undergone Cardiac Resynchronisation Therapy (CRT) in the last 6 months and no planned CRT;
• Implantable cardioverter defibrillator (ICD) implant planned during the study;
• Hypersensitivity to sulfur or related compounds;
• Renal insufficiency defined as estimated Glomerular Filtration Rate (eGFR) < 30 mL/minute/1.73 m2 (Modification of Diet in Renal Disease Study MDRD) [2];
• Life expectancy less than 6 months;
• Active malignancy requiring active anti-neoplastic therapy that will, in the opinion of the investigator, interfere with study treatment or participation. (Stable basal cell skin cancer and cancers being treated solely with hormonal therapy are allowed.)
• Inability to speak English (due to need to administer standardized English-language questionnaire); or
• Any other chronic illness that may, in the opinion of the Investigator, increase the risks associated with this trial.